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Using Synbiotics as a Therapy to Protect Mental Health in Alzheimer's Disease
Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea
Correspondence to:J. Microbiol. Biotechnol. 2024; 34(9): 1739-1747
Published September 28, 2024 https://doi.org/10.4014/jmb.2403.03021
Copyright © The Korean Society for Microbiology and Biotechnology.
Abstract
Keywords
Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative illness that impairs neurocognitive function and impedes mental capacity development [1]. In 2020, approximately 5.8 million individuals were diagnosed with AD in America. This disease initially manifests as mild memory loss and gradually progresses to the loss of conversational ability and responsiveness to the environment. It primarily affects the parts of the brain responsible for thought, memory, and language [2].
Understanding the pathophysiology of AD and developing effective therapeutics are multifaceted fields of study. The etiology of AD involves various factors, including mitochondrial dysfunction, oxidative stress (OS), lipid peroxidation, reactive oxygen species (ROS), and DNA/RNA/protein oxidation. The progression of AD is also influenced by disruptions in energy metabolism and calcium homeostasis, as well as neuroinflammation and neuronal death [3]. Verbal and visual memory deficiencies have been associated with psychiatric illnesses such as anxiety, which are also related to decreased hippocampal volume and function in AD [4, 5]. Anxiety is an early symptom of AD, and several studies have established the correlation between anxiety and AD pathology biomarkers [6]. Individuals experiencing anxiety have shown positive amyloid scans and mesial temporal entorhinal alterations, which include atrophy, hypometabolism, and presence of neurofibrillary tangles [7]. In the context of AD, anxiety is attributed to multifactorial causes, such as neurobiological factors and psychological influences, including cognitive deficits and external stresses [6].
The concept of a “synbiotic” was initially introduced by Gibson and Roberfroid [8] to denote a synergistic combination of probiotics and prebiotics. Synbiotics were developed to overcome potential challenges in the survival of probiotics in the intestinal system and achieve the beneficial qualities of probiotics and prebiotics. Consequently, a well-balanced combination of these elements in one product yields outcomes superior to the individual activities of probiotics or prebiotics alone [2]. In recent years, studies on neurodegenerative pathology have focused on prebiotic, probiotic, and synbiotic nutrition [9]. The concept of “psychobiotics” has also emerged, thereby highlighting the mental health benefits of probiotics. The consumption of psychobiotics positively affects the gut–brain-mediated nervous system through various mechanisms, including neuroendocrine, neuroimmunological, and enteric pathways [10]. These effects help improve the functioning of the gastrointestinal and central nervous systems [10]. Numerous preclinical studies and clinical trials on AD have demonstrated the beneficial effects of probiotics and prebiotics. However, few studies have explored the use of synbiotics for the treatment of AD and mental health.
This review aims to explore the potential pathways that could serve as targets for the treatment of AD and to elucidate the health-promoting benefits of synbiotics on mental health. It also addresses the limitations that should be further studied.
Hypotheses Describing the Fundamental Mechanisms Underlying AD
With the understanding of the molecular causes of AD, potential medications that can inhibit the progression of this debilitating condition have been developed. Several hypotheses, including the amyloid cascade, hyperphosphorylated tau protein, metal ion, cholinergic and OS hypotheses, have been proposed as fundamental mechanisms of AD (Fig. 1). In this section, we discuss these widely accepted concepts and explore clinical studies to evaluate their validity.
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Fig. 1. Mechanisms underlying Alzheimer’s disease. It describes how synbiotics affects Alzheimer's disease through microbiota-gut-brain axis. The good probiotics could reduce inflammation, inhibit ROS, reduce the Aβ plaque formation and increase protective molecules such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Meanwhile, signals from the brain help stimulate the production of short-chain fatty acids (SCFAs), serotonin and reduce proinflammatory cytokines in the gut.
Amyloid Cascade Hypothesis
According to the amyloid cascade hypothesis, first proposed in 1991, the abnormal accumulation of amyloid β (Aβ) plaques in different brain regions contributes to neurodegeneration in AD. Aβ plaques act as triggers for a cascade of events, including neurotic damage [11], formation of neurofibrillary tangles through tau protein, neuronal dysfunction, and cell death [12]. This process stimulates microglia and astrocytes, resulting in inflammatory and oxidative responses. Ultimately, neuronal malfunction and apoptosis may lead to AD development (Fig. 2A).
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Fig. 2. Pathogenesis of Alzheimer’s disease. (A) Amyloid beta (Aβ) cascade hypothesis; (B) hyperphosphorylated tau protein hypothesis; (C) metal ion hypothesis; and (D) oxidative stress hypothesis.
Aβ can activate tau protein kinase 1; consequently, it triggers the abnormal phosphorylation of tau protein and causes the formation of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs). Because of these pathological changes, the progression of tau pathology in AD further accelerates [13]. Furthermore, certain genetic factors considerably influence the onset and progression of AD [14]. Genes such as APP, PSEN-1, and PSEN-2 are strongly associated with AD pathology and can cause abnormal Aβ production [15]. Clinical research has devoted remarkable efforts to developing novel anti-AD drugs. Although approved medications provide symptomatic relief, they do not alter the disease course. These medications are often related to critical adverse effects and should only be used in severe cases. Therefore, ongoing research focuses on amyloid-based therapeutics to provide potentially effective treatments for this disease. Interventions based on the Aβ hypothesis aim to reduce Aβ production and aggregation while enhancing its clearance.
Hyperphosphorylated tau Protein Hypothesis
Tau protein is a family of six highly soluble protein isoforms encoded by the microtubule-associated protein tau gene. They preserve the stability of microtubules in axons and are widely distributed in neurons in the central nervous system (CNS). Conversely, they are less prevalent in oligodendrocytes and astrocytes, which are immune cells in the brain [16]. When tau undergoes atypical phosphorylation, normal adult tau is converted into PHF-tau. Then, these insoluble filaments accumulate and form NFTs, a characteristic hallmark of AD [17].
Various approaches have been explored to inhibit tau protein and consequently prevent neurodegenerative diseases, including AD. In one strategy, protein kinases are modified to prevent the abnormal hyperphosphorylation of tau. By targeting these kinases, researchers aim to maintain the normal phosphorylation state of tau and prevent neurofibrillary tangle formation. In another approach, anti-inflammatory treatments are used to alleviate brain inflammation, which has been implicated in tau hyperphosphorylation and aggregation (Fig. 2B) [18].
Metal ion Hypothesis
Metal ions, such as zinc and copper, participate in neuronal activity and the functioning of metalloproteins within synapses (Fig. 2C). These ions maintain normal brain cell function and synaptic transmission. However, disturbances in the homeostasis of metal ions or the accumulation of metals without known biological functions can disrupt the ionic balance and favor the development of neurodegenerative disorders, including AD [19].
The function of metal ions in AD has been elucidated for their use in potential therapeutic strategies. For example, the pathological effects associated with Aβ and tau protein aggregation may be mitigated by modulating metal ion concentrations or developing agents that can target metal ion imbalances. AD progression may be slowed down, and its debilitating effects may be alleviated by maintaining proper metal ion homeostasis and preventing metal-induced toxicity. However, further research and clinical investigations are needed to understand the complex relationship of metal ions with AD and to develop effective treatments targeting these mechanisms.
OS Hypothesis
OS is characterized by the accumulation of various compounds and free radicals derived from molecular oxygen. With aging, OS increases in the brain and causes a redox imbalance, which is attributed to the overproduction of ROS or a deficiency in the antioxidant system [20]. In the context of AD, OS is implicated in disease pathogenesis, triggering free radical production through processes such as dysfunction of the mitochondria and disruption of transition metal homeostasis (Fig. 2D). These free radicals lead to neurotoxicity mediated by Aβ and tau proteins [21].
OS has been implicated as a potential source of Aβ accumulation. In neuronal and non-neuronal cells, oxidants and oxidative byproducts can enhance the expression of amyloid precursor protein (APP) and increase the intracellular and released levels of Aβ [22]. Furthermore, Aβ promotes the release of endothelin-1 (ET-1), a peptide that binds to ETA receptors and reduces ROS levels. However, this binding leads to the release of calcium ions (Ca2+), thereby constricting pericytes and brain capillaries. Consequently, this constriction decreases the supply of glucose and oxygen in brain tissues and potentially contributes to the development of neuropsychiatric disorders [23]. Furthermore, the homeostasis of metals, including copper, zinc, and iron, can be disrupted by OS, and such disruption is closely linked to neural activity. These disturbances in metal homeostasis and abnormal interactions between Aβ and metal ions have been implicated in the development of Aβ deposition in the brains of individuals with AD. OS also considerably affect tau protein by promoting its hyperphosphorylation and polymerization [24]. Collectively, these findings suggest that reducing or eliminating ROS can potentially delay the onset or slow the progression of AD through various mechanisms. Natural antioxidants may help prevent or treat AD by targeting multiple distinct molecular mechanisms involved in the development and progression of AD.
Modulation of the Gut Microbiota–Brain Axis
The gut–brain axis (GBA) functions as a bidirectional communication system that connects the central and enteric neural systems and bridges the emotional and cognitive regions of the brain with peripheral functions of the intestine [25]. This axis preserves homeostasis in the digestive system, central nervous system, and gut microbiota [26]. Communication between the digestive system and the central brain involves various connections, including chemical mediators, neuronal networks, and the immune system [27].
The chemical communication between the gut microbiota and the nervous system is a critical aspect achieved through direct interactions involving short-chain fatty acids (SCFAs) and indirect chemical signaling pathways [27]. Numerous studies have emphasized that SCFAs influence the central nervous system by modulating neurotransmitter and neurotrophic factor levels. For instance, Schroeder
Studies on the equilibrium of innate immune system cells within the brain have shown that the bidirectional communication between the central nervous system and gut bacteria occurs through the immune pathway [30, 31]. Certain immune cells, such as T and B cells, considerably influence brain function. For instance, T cells are associated with various complex brain functions, including spatial working memory, cognition, emotion, and stress response [32], and B cells recruit peripheral immune cells to the injured brain [33]. The blood–brain barrier (BBB) limits the access of circulating T and B cells to the underlying parenchyma; as a result, immune modulation within the CNS is mediated by microglia, astrocytes, and oligodendrocytes [34]. The gut microbiome regulates and modifies the development and functioning of microglia [35]. Therefore, understanding the effect of the gut microbiota on the immune system and the CNS can provide valuable insights into potential therapeutic interventions for neurodegenerative diseases, including AD.
Synbiotics in Pharmaceutical Supplements for AD
Probiotics, which include bacteria that considerably affect human health, and prebiotics, which are fiber-based compounds that serve as nourishment for probiotics, can be combined to form synbiotics [36]. Well-known probiotic strains in the genus
In addition to the influence of probiotics, the effects of prebiotic components, such as fructooligosaccharides (FOS), which naturally occur in various fruits and vegetables, have been investigated in relation to cognitive deficits [40]. Chen
Xylooligosaccharides (XOS) have also been widely explored and have shown equally promising results. Han
Administering prebiotic and probiotic formulations in the diet of AD rats has favorable effects, including improved brain function caused by the reduction of gastrointestinal inflammation, OS in the hippocampus, and microglial activation [42]. Consequently, the combination of prebiotics and probiotics shows potential for enhancing the efficacy in reducing AD-related indicators.
Previous studies revealed that a high intake of prebiotics and probiotics, along with other nutrients, is associated with a slower cognitive decline and a reduced risk of AD [43]. Table 1 provides additional details regarding the diverse effects of synbiotic formulations.
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Table 1 . Effects of synbiotics on AD models.
Synbiotics Subject/Model Dose and duration Effects References In vitro experiments Lactobacillus plantarum ,Bifidobacterium infantis , andL. salivarius with grapeseed polyphenolic extractIn vitro model of the human gastrointestinal tract N/A ■ Inhibited the aggregation of amyloid plaques and tau fibrils
■ Exhibited anti-inflammatory activitiesPasinetti [44] In vivo experiments on mice L. plantarum 69-2 with GOSMale BALB/c mice aged 8 weeks were injected with 50 mg/ml Dgalactose per day for 6 weeks ■ 500 mg/kg GOS every day
■ 5×109 CFU kg/lL. plantarum 69-2 per day
■ Combination of 500 mg GOS and 5 × 109 CFUL. plantarum 69-2 daily■ Increased the total antioxidant capacity (T-AOC) and glutathione (GSH) activities, leading to enhanced antioxidant capacity in the liver
■ Decreased the amount ofProteobacteria in the stomach and considerably increased the quantity ofVerrucomicrobia and the levels of SCFA (acetate, propionate, and butyrate)
■ Repressed the gene expression of AMP-activated protein kinases (AMPK1 and AMPK2) and sirtuin 1 (SIRT1) and significantly increased the levels of aging-related genes, such as Bax, P53, and nuclear factor kappa-B (NF-κB), which might be attributed to the promotion of the AMPK/SIRT1 pathway, potentially regulating the expression of aging-related genesWang et al . [45]L. plantarum NCIMB 8826,Lactobacillus fermentum NCIMB 5221, andBifidobacterium longum spp.infantis withEmblica officinalis ,Terminalia bellirica , andTerminalia chebula powderDrosophila melanogaster with transgenic BACE1-APP gene■ 3.0 × 109 CFU/ml of each type of bacteria mixed with 0.5% of TFLA powder for 30 days ■ Slowed down acetylcholinesterase growth and improved survival
■ Inhibited the development of the pathogensS. aureus andE. coli
■ Increased the amount of total triglycerides because of the increased gene expression of acetyl CoA carboxylase after 30 days
■ Decreased the expression of lipid peroxidationWestfall et al . [46]Lactobacillus paracasei HII01 with XOSMale Wistar rats fed with a high-fat diet or normal diet ■ 2 ml of the combination of 10% XOS and 108 CFU L. paracasei HII01 for 12 weeks■ Reduced the mRNA expression levels of the proinflammatory cytokines interleukin (IL)-1 and IL-6
■ Prevented hippocampal dysplasia via LTP development and enhanced the dendritic spine density
■ Improved brain mitochondrial dysfunction, reduced hippocampus oxidative stress, and elicited anti-apoptotic effectsChunchai et al . [47]Lactobacillus rhamnosus UBLR-58 with curcuminMice with scopolamineinduced memory impairment ■ 1 ml/kg/day for 10 days ■ Increased antioxidant enzyme levels
■Minimized neuronal damage
■ Improved memory and cognitive functions in the behavioral studyPatel et al . [48]Prebiotics mixed with Vitalon Probiotics powder (v/v: 7/1) APP transgenic mice ■ 4.1 g/kg/day for 2months ■ Decreased the accumulation level of Aβ42
■ Did not change Aβ40
■ Reduced the TNF-α gene expression but did not affect IL-1βDeng et al . [49]In vivo experiments on humans Lactobacillus acidophilus ,Bifidobacterium bifidum , andB. longum with seleniumPatients with AD ■ 200 μg/day for 12 weeks ■ Improved cognitive function
■ Influenced the MMSE score, hs-CRP, TAC, GSH, insulin metabolism markers, triglycerides, VLDL-, LDL-, and total-/HDL-cholesterol
■ Improved the gene expression of TNF-a, PPAR-g, and LDLRTamtaji et al . [50]Milk supplemented with kefir grains Human ■ 2 ml per kilogram of body weight every day for 90 days ■ Favored cognitive improvement in the memory, language, construction ability, and attentional function assessments of patients after 90 days
■ Decreased the levels of O2-, H2O2, and ONOO-/OH- levels and increased the levels of NO and the oxidation–reduction of proteinsTon et al . [51]Lactobacillus acidophilus T16,B. bifidum BIA-6,Bifidobacterium lactis BIA-7, andB. longum BIA with maltodextrinPatients with high depression ■ 5 g of probiotics, 5 g of synbiotics, and 20 g of prebiotics in for weeks ■ Significantly increased the brain-derived neurotrophic factor in the synbiotic group compared with that in the probiotic and maltodextrin-only groups Haghighat et al . [52]
Prevention of AD by Neuroinflammation
The relationship between cytokines and AD has been established [43]. According to the amyloid cascade hypothesis, Aβ activates microglia and inflammatory cytokines [54]. In the prodromal phase of AD, soluble Aβ oligomers can decrease synaptic plasticity, impede potentiation, and stimulate microglia [55]. Neuroinflammation and pro-inflammatory cytokines enhance tau phosphorylation and decrease synaptic concentrations; consequently, cellular instability and neuronal death occur [56]. Aβ stimulates microglial receptors, which cause the release of cytokines, chemokines, and reactive oxygen species [57]. Additionally, when Aβ binds to the receptor for advanced glycation end products, inflammation occurs, and the release of pro-inflammatory cytokines such as TNFα and IL-6 is promoted [58]. Hence, the administration of anti-inflammatories can be a promising technique to prevent the incidence and progression of AD. The cytokine balance has been a focal point in understanding the etiology of AD and identifying potential new treatment targets. As illustrated in Table 1, the consumption of kefir-fermented milk considerably reduces systemic inflammation mediated by pro-inflammatory cytokines, such as IL-8, IL-12, and TNF-α [51]. TNF-α particularly participates in the inflammatory cascade and exacerbates the Aβ and tau pathology in patients with AD [59]. Short-term anti-TNF-α therapy can reduce pathology and improve cognition in these patients [60]. Similarly, the neurogenesis levels of Aβ42 in APP mice fed with only the combination of prebiotics and Vitalon Probiotics powder decrease compared with those in prebiotic-treated and control mice [49]. TNF-α levels are also reduced, but IL-1β levels remain unchanged [49].
The increased levels of the p40 subunit of IL-12 have been associated with the onset of AD [61]. Conversely, the decreased levels of IL-12 and p40 may mitigate cognitive decline and AD-related pathologies [62]. Kefir milk supplementation causes a decrease in pro-inflammatory activity and simultaneously balances pro- and anti-inflammatory cytokine levels [51]. Furthermore, IL-1β and IL-6 have been implicated in AD risk [54]. IL-1β overexpression inhibits the activity of the cholinergic system and promotes the accumulation of Aβ and NFT in AD [63]. Excessive IL-6 influences the cdk5/p53 pathway, thereby triggering tau phosphorylation [57]. Wang
Prevention of AD via OS
Serum levels of OS biomarkers are increased in patients with neurodegenerative disorders; as such, they can be used to evaluate the effectiveness of novel therapeutic approaches for patients with AD [67]. ROS plays direct and indirect roles in the pathophysiology of AD. For instance, increased levels of free radicals, such as O2, H2O2, and NO, can damage proteins, lipids, and nucleic acids; consequently, mitochondrial degeneration and neurotoxicity occur [68]. Additionally, OS is related to Aβ-induced neurodegeneration in patients with AD [69]. BDNF serum levels are also closely correlated with AD. BDNF is an endogenous protein involved in brain function, synaptic plasticity, and structural integrity [70]. A reduced BDNF level is considered a hallmark of AD; therefore, BDNF is considered an important pathway in AD treatment [71]. In a 12-week randomized clinical trial, Haghighat et al. [52] compared the effects of consuming synbiotic supplementation with
Kefir treatment considerably reduces protein oxidation. Notably, kefir supplementation also decreases blood ROS availability and increases NO levels, indicating that plasma protein oxidation is reduced in patients with AD. Chunchai
Prevention of AD by SCFAs and Other Substances
SCFAs play a crucial role in controlling neuroinflammatory processes implicated in dementia disorders, including AD. They participate in energy metabolism and thus help compensate for any metabolic deficiencies in the brain [72]. Yilmaz
Westfall
Depression is considered an early symptom and risk factor for AD diagnosis. Individuals who have experienced depressive episodes in the past more likely develop AD later in life compared with those without a history of depression [79]. This observation highlights the importance of mental health in the context of neurological disorders. Furthermore, changes in the gut microbiota have been associated with variations in the progression of neurodegenerative diseases, including AD [80]. Tamtaji
Future Concerns about Synbiotics for the Prevention of AD
Synbiotic medication shows therapeutic potential for AD; however, several limitations should be addressed before it can be recommended in medical practice. First, consuming probiotics has raised concerns on its potential adverse effects, including sepsis, hypersensitivity reactions, and gene transfer leading to pathogenic antibiotic resistance [81]. Another study specifically warns against the use of probiotics in patients with AD receiving immunosuppressive therapies such as chemotherapy because of cases of fungal blood infections and sepsis in recipients of
Second, the effects of probiotics exhibit individual variability [83]. Because of this variability, determining which specific probiotic within a multi-probiotic treatment is responsible for observed outcomes becomes challenging. Some studies have suggested that using probiotics after antibiotic treatment can increase the risk of contracting infectious diseases by causing persistent dysbiosis [84]. Probiotics can metabolize tryptophan, which substantially raises the risk of serotonin syndrome in combination with potent selective serotonin reuptake inhibitors [41]. The effects of serotonin syndrome can range from mild symptoms, such as shivering and diarrhea, to severe manifestations, including muscle rigidity, fever, seizures, and even death [85]. Therefore, a limited number of studies have investigated the application of probiotics and synbiotics as a medical intervention for AD. Extreme caution should be exercised when considering their use in humans, particularly in the elderly and individuals with multiple comorbidities.
Lastly, the potential negative effects of prebiotics on AD have not been extensively studied. However, certain prebiotics may contribute to neuroinflammation. For example, lactulose, a prebiotic, is associated with reduced short-term memory and impaired learning capacity in mice with AD [86]. To address these concerns and mitigate potential risks, researchers should conduct further long-term studies on the mechanisms, benefits, and drawbacks of synbiotics. Obtaining additional evidence supporting their safety and efficacy will enhance their reliability and maximize their potential for pharmaceutical and medical applications to prevent and manage AD.
Conclusion
Synbiotics have shown promising results in improving microbiome stability and surpassing the individual use of probiotics or prebiotics alone. They positively affect brain health, particularly the prevention of neurodegenerative diseases such as AD. They may mitigate or even reverse the primary symptoms of AD through various mechanistic pathways, such as reducing chronic neuroinflammation, modulating peripheral factors, influencing the production and translation of neurotoxic metabolites, regulating gut microbiota, and reducing OS. However, further studies should be performed to fully understand the etiology of AD and reveal the mechanisms by which synbiotics exert their effects.
The encouraging outcomes described in this review support the potential use of synbiotics as an effective medical therapy for AD. Nonetheless, further research is required to elucidate their precise mode of action and establish stronger connections between microbial and AD research. Continued investigation will help clarify their therapeutic mechanisms and optimize their application in AD prevention and treatment.
Conflict of Interest
The authors have no financial conflicts of interest to declare.
References
- Srivastava S, Ahmad R, Khare SK. 2021. Alzheimer's disease and its treatment by different approaches: a review.
Eur. J. Med. Chem. 216 : 113320. - Haghighat N, Mohammadshahi M, Shayanpour S, Haghighizadeh MH, Rahmdel S, Rajaei M. 2021. The effect of synbiotic and probiotic supplementation on mental health parameters in patients undergoing hemodialysis: a double-blind, randomized, placebocontrolled trial.
Indian J. Nephrol. 31 : 149. - Talebi M, Kakouri E, Talebi M, Tarantilis PA, Farkhondeh T, İlgün S,
et al . 2021. Nutraceuticals-based therapeutic approach: recent advances to combat pathogenesis of Alzheimer's disease.Exp. Rev. Neurother. 21 : 625-642. - DeCarolis NA, Eisch AJ. 2010. Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation.
Neuropharmacology 58 : 884-893. - Ravetz RS. 1999. Psychiatric disorders associated with Alzheimer's disease.
J. Am. Osteopath. Assoc. 99 : S13-16. - Mendez MF. 2021. The relationship between anxiety and Alzheimer's disease1.
J. Alzheimer's Disease Rep. 5 : 171-177. - Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT,
et al . 2021. Alzheimer disease.Nat. Rev. Dis. Primers 7 : 33. - Gibson GR, Probert HM, Van Loo J, Rastall RA, Roberfroid M. 2004. Dietary modulation of the human colonic microbiota: updating the concept of prebiotics.
Nutr. Res. Rev. 17 : 259-275. - Dinan TG, Stanton C, Cryan JF. 2013. Psychobiotics: a novel class of psychotropic.
Biol. Psychiatry 74 : 720-726. - Cheng L, Liu YW, Wu CC, Wang S, Tsai Y. 2019. Psychobiotics in mental health, neurodegenerative and neurodevelopmental disorders.
J. Food Drug Anal. 27 : 632-648. - Lustbader JW, Cirilli M, Lin C, Xu H, Takuma K, Wang N,
et al . 2004. ABAD directly links ASS to mitochondrial toxicity in Alzheimer's disease.Science 304 : 448-452. - Hunt D, Castillo PE. 2012. Synaptic plasticity of NMDA receptors: mechanisms and functional implications.
Curr. Opin. Neurobiol. 22 : 496-508. - Vergara C, Houben S, Suain V, Yilmaz Z, De Decker R, Vanden Dries V,
et al . 2019. Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo.Acta Neuropathol. 137 : 397-412. - Bertram L, Tanzi RE. 2008. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.
Nat. Rev. Neurosci. 9 : 768-778. - Shen J, Kelleher RJ. 2007. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism.
Proc. Natl. Acad. Sci. USA 104 : 403-409. - Michalicová A, Majerová P, Kováč A. 2020. TAU protein and its role in blood-brain barrier dysfunction.
Front. Mol. Neurosci. 13 : 570045. - Medeiros R, Baglietto‐Vargas D, LaFerla FM. 2011. The role of TAU in Alzheimer's disease and related disorders.
CNS Neurosci. Ther. 17 : 514-524. - Iqbal K, Liu F, Chen G, Grundke‐Iqbal I. 2010. Tau in Alzheimer disease and related tauopathies.
Curr. Alzheimer Res. 7 : 656-664. - Budimir A. 2011. Metal ions, Alzheimer's disease and chelation therapy.
Acta Pharm. 61 : 1-14. - Nita M, Grzybowski A. 2016. The role of the reactive oxygen species and oxidative stress in the pathomechanism of the Age-Related ocular diseases and other pathologies of the anterior and posterior eye segments in adults.
Oxid. Med. Cell. Longevity 2016 : 1-23. - Zhao Y, Zhao B. 2013. Oxidative stress and the pathogenesis of Alzheimer's disease.
Oxid. Med. Cell. Longev. 2013 : 1-10. - Guglielmotto. 2010. Oxidative stress mediates the pathogenic effect of different Alzheimer's disease risk factors.
Front. Aging Neurosci. : 10. doi: 10.3389/neuro.24.003.2010.eCollection 2010. - Fan L, Mao C, Hu X, Zhang S, Yang Z, Hu ZW,
et al . 2020. New insights into the pathogenesis of Alzheimer's disease.Front. Neurol. 10 : 1312. - Haque MdM, Murale DP, Kim YK, Lee JH. 2019. Crosstalk between oxidative stress and tauopathy.
Int. J. Mol. Sci. 20 : 1959. - Martin CR, Osadchiy V, Kalani A, Mayer EA. 2018. The brain-gut-microbiome axis.
Cell. Mol. Gastroenterol. Hepatol. 6 : 133-148. - Carabotti M, Scirocco A, Maselli MA, Severi C. 2015. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.
Ann. Gastroenterol. 28 : 203-209. - Morais LH, Schreiber HL, Mazmanian SK. 2020. The gut microbiota-brain axis in behaviour and brain disorders.
Nat. Rev. Microbiol. 19 : 241-255. - Schroeder FA, Lin CL, Crusio WE, Akbarian S. 2007. Antidepressant-Like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse.
Biol. Psych. 62 : 55-64. - Frost G, Sleeth M, Sahuri-Arisoylu M, Lizarbe B, Cerdán S, Brody L,
et al . 2014. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism.Nat. Commun. 5 : 3611. - Louveau A, Smirnov I, Keyes T, Eccles JD, Rouhani SJ, Peske JD,
et al . 2015. Structural and functional features of central nervous system lymphatic vessels.Nature 523 : 337-341. - Yoo BH, Mazmanian SK. 2017. The enteric network: interactions between the immune and nervous systems of the gut.
Immunity 46 : 910-926. - Morimoto K, Nakajima K. 2019. Role of the immune system in the development of the central nervous system.
Front. Neurosci. 13 : 916. - Ortega SB, Torres V, Latchney SE, Whoolery CW, Noorbhai I, Poinsatte K,
et al . 2020. B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice.Proc. Natl. Acad. Sci. USA 117 : 4983-4993. - Erny D, De Angelis ALH, Jaitin DA, Wieghofer P, Staszewski O, David E,
et al . 2015. Host microbiota constantly control maturation and function of microglia in the CNS.Nat. Neurosci. 18 : 965-977. - Mukherjee S, Joardar N, Sengupta S, Babu SPS. 2018. Gut microbes as future therapeutics in treating inflammatory and infectious diseases: lessons from recent findings.
J. Nutr. Biochem. 61 : 111-128. - Bonfili L, Cecarini V, Berardi S, Scarpona S, Suchodolski JS, Nasuti C,
et al . 2017. Microbiota modulation counteracts Alzheimer's disease progression influencing neuronal proteolysis and gut hormones plasma levels.Sci. Rep. 7 : 2426. - Archie SR, Shoyaib AA, Cucullo L. 2021. Blood-brain barrier dysfunction in CNS disorders and putative therapeutic targets: an overview.
Pharmaceutics 13 : 1779. - Kobayashi Y, Sugahara H, Shimada K, Mitsuyama E, Kuhara T, Yasuoka A,
et al . 2017. Therapeutic potential ofBifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer's disease.Sci. Rep. 7 : 13510. - Kobayashi Y, Kuhara T, Oki M, Xiao J. 2019. Effects of
Bifidobacterium breve A1 on the cognitive function of older adults with memory complaints: a randomised, double-blind, placebo-controlled trial.Benef. Microbes 10 : 511-520. - Han D, Li Z, Liu T, Yang N, Li Y, He J,
et al . 2020. Prebiotics regulation of intestinal microbiota attenuates cognitive dysfunction induced by surgery stimulation in APP/PS1 mice.Aging Dis. 11 : 1029. - Arora K, Green M, Prakash S. 2020. The microbiome and Alzheimer's disease: potential and limitations of prebiotic, synbiotic, and probiotic formulations.
Front. Bioeng. Biotechnol. 8 : 537847. - Pistollato F, Iglesias RC, Ruíz R, Aparicio S, Crespo J, López LAD,
et al . 2018. Nutritional patterns associated with the maintenance of neurocognitive functions and the risk of dementia and Alzheimer's disease: a focus on human studies.Pharmacol. Res. 131 : 32-43. - Chen D, Yang X, Yang J, Lai G, Yong T, Tang X,
et al . 2017. Prebiotic effect of fructooligosaccharides from morinda officinalis on Alzheimer's disease in rodent models by targeting the microbiota-gut-brain axis.Front. Aging Neurosci. 9 : 403. - Pasinetti GM. 2020. Synbiotic-derived metabolites reduce neuroinflammatory symptoms of Alzheimer's disease.
Curr. Dev. Nutr. 4 : nzaa062_035. - Wang W, Liu F, Xu C, Liu Z, Ma J, Gu L,
et al . 2021.Lactobacillus plantarum 69-2 Combined with galacto-oligosaccharides alleviates d-galactose-induced aging by regulating the AMPK/SIRT1 signaling pathway and gut microbiota in mice.J. Agric. Food Chem. 69 : 2745-2757. - Westfall S, Lomis N, Prakash S. 2019. A novel synbiotic delays Alzheimer's disease onset via combinatorial gut-brain-axis signaling in
Drosophila melanogaster .PLoS One 14 : e0214985. - Chunchai T, Thunapong W, Yasom S, Wanchai K, Eaimworawuthikul S, Metzler G,
et al . 2018. Decreased microglial activation through gut-brain axis by prebiotics, probiotics, or synbiotics effectively restored cognitive function in obese-insulin resistant rats.J. Neuroinflammation 15 : 11. - Patel C, Patel C, Acharya S. 2020. Potentiation of anti-Alzheimer activity of curcumin by probiotic
Lactobacillus rhamnosus UBLR-58 against scopolamine-induced memory impairment in mice.Naunyn-Schmiedeberg's Arch. Pharmacol. 393 : 1955-1962. - Deng S, Chen C, Lin H, Cheng IH. 2021. The beneficial effect of synbiotics consumption on Alzheimer's disease mouse model via reducing local and systemic inflammation.
IUBMB Life 74 : 748-753. - Tamtaji OR, Heidari‐Soureshjani R, Mirhosseini N, Kouchaki E, Bahmani F, Aghadavod E,
et al . 2019. Probiotic and selenium cosupplementation, and the effects on clinical, metabolic and genetic status in Alzheimer's disease: a randomized, double-blind, controlled trial.Clin. Nutr. 38 : 2569-2575. - Ton AMM, Campagnaro BP, Alves GA, Aires R, Côco LZ, Arpini CM,
et al . 2020. Oxidative stress and dementia in Alzheimer's patients: effects of synbiotic supplementation.Oxid. Med. Cell. Longev. 2020 : 2638703. - Haghighat N, Rajabi S, Mohammadshahi M. 2019. Effect of synbiotic and probiotic supplementation on serum brain-derived neurotrophic factor level, depression and anxiety symptoms in hemodialysis patients: a randomized, double-blinded, clinical trial.
Nutr. Neurosci. 24 : 490-499. - Su F, Bai F, Zhang Z. 2016. Inflammatory cytokines and Alzheimer's disease: a review from the perspective of genetic polymorphisms.
Neurosci. Bull. 32 : 469-480. - Garcez ML, Mina F, Bellettini-Santos T, Carneiro FG, Amparo L, Schiavo GL,
et al . 2017. Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid β (1-42) in mice.Prog. Neuropsychopharmacol. Biol. Psychiatry 77 : 23-31. - Selkoe DJ, Hardy J. 2016. The amyloid hypothesis of Alzheimer's disease at 25 years.
EMBO Mol. Med. 8 : 595-608. - Quintanilla RA, Orellana D, González-Billault C, Maccioni RB. 2004. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway.
Exper. Cell Res. 295 : 245-257. - Khoury JE, Moore KJ, Means TK, Leung JH, Terada K, Toft M,
et al . 2003. CD36 mediates the innate host response to Β-Amyloid.J. Exper. Med. 197 : 1657-1666. - Chellappa RC, Lukose B, Rani P. 2020. G82S RAGE polymorphism influences amyloid-RAGE interactions relevant in Alzheimer's disease pathology.
PLoS One 15 : e0225487. - Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S,
et al . 2008. Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTG-AD mice.Am. J. Pathol. 173 : 1768-1782. - McAlpine FE, Lee J, Harms AS, Ruhn KA, Blurton‐Jones M, Hong JJ,
et al . 2009. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology.Neurobiol. Dis. 34 : 163-177. - Berg JV, Prokop S, Miller KR, Obst J, Kälin RE, Lopategui-Cabezas I,
et al . 2012. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline.Nat. Med. 18 : 1812-1819. - Liu L, Xu Y, Liu Z, Chen JG, Zhang Y, Zhu J,
et al . 2011. IL12 polymorphisms, HBV infection and risk of hepatocellular carcinoma in a high‐risk Chinese population.Int. J. Cancer 128 : 1692-1696. - Halder N, Lal G. 2021. Cholinergic system and its therapeutic importance in inflammation and autoimmunity.
Front. Immunol. 12 : 660342. - Shah S, Yoon GH, Chung S, Abid MN, Kim TH, Lee HY,
et al . 2016. Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer's disease neuropathological deficits.Mol. Psychiatry 22 : 407-416. - Assefa BT, Tafere GG, Wondafrash DZ, Gidey MT. 2020. The bewildering effect of AMPK activators in Alzheimer's disease: review of the current evidence.
BioMed Res. Int. 2020 : 9895121. - Zhang M, Tang Z. 2023. Therapeutic potential of natural molecules against Alzheimer's disease via SIRT1 modulation.
Biomed. Pharmacother. 161 : 114474. - Manoharan S, Guillemin GJ, Abiramasundari RS, Essa MM, Akbar M. 2016. The role of reactive oxygen species in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease: a mini review.
Oxid. Med. Cell. Longev. 2016 : 8590578. - Oliver D, Reddy PH. 2019. Small molecules as therapeutic drugs for Alzheimer's disease.
Mol. Cell. Neurosci. 96 : 47-62. - Drake J, Link CD, Butterfield DA. 2003. Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid β-peptide (1-42) in a transgenic
Caenorhabditis elegans model.Neurobiol. Aging 24 : 415-420. - Laske C, Stransky E, Leyhe T, Eschweiler GW, Maetzler W, Wittorf A,
et al . 2007. BDNF serum and CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls.J. Psychiatr. Res. 41 : 387-394. - Mori Y, Tsuji M, Oguchi T, Kasuga K, Kimura A, Futamura A,
et al . 2021. Serum BDNF as a potential biomarker of Alzheimer's disease: verification through assessment of serum, cerebrospinal fluid, and medial temporal lobe atrophy.Front. Neurol. 12 : 653267. - Zilberter Y, Zilberter M. 2017. The vicious circle of hypometabolism in neurodegenerative diseases: ways and mechanisms of metabolic correction.
J. Neurosci. Res. 95 : 2217-2235. - Yılmaz A, Geddes TJ, Han B-S, Wilson GD, Imam K, Maddens M,
et al . 2017. Diagnostic biomarkers of Alzheimer's disease as identified in saliva using 1H NMR-based metabolomics.J. Alzheimer's disease 58 : 355-359. - Cui M, Jiang Y, Zhao Q, Zhu Z, Liang X, Zhang K,
et al . 2020. Metabolomics and incident dementia in older Chinese adults: the Shanghai aging study.Alzheimers Dement. 16 : 779-788. - Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti GM. 2017. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms.
Exp. Rev. Neurother. 18 : 83-90. - Fernando WMADB, Martins I, Morici M, Bharadwaj P, Rainey-Smith SR, Lim WLF,
et al . 2020. Sodium butyrate reduces brain amyloid-Β levels and improves cognitive memory performance in an Alzheimer's disease transgenic mouse model at an early disease stage.J. Alzheimer's Dis. 74 : 91-99. - Filippone A, Lanza M, Campolo M, Casili G, Paterniti I, Cuzzocrea S,
et al . 2020. Protective effect of sodium propionate in Aβ1-42 -induced neurotoxicity and spinal cord trauma.Neuropharmacology 166 : 107977. - Westfall S, Lomis N, Prakash S. 2018. A novel polyphenolic prebiotic and probiotic formulation have synergistic effects on the gut microbiota influencing
Drosophila melanogaster physiology.Artif. Cells Nanomed. Biotechnol. 46 : 441-455. - Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. 2006. Depression and risk for Alzheimer disease.
Arch. Gen. Psych. 63 : 530. - Methiwala HN, Vaidya B, Addanki VK, Bishnoi M, Sharma SS, Kondepudi KK. 2021. Gut microbiota in mental health and depression: role of pre/pro/synbiotics in their modulation.
Food Funct. 12 : 4284-4314. - Ayichew T, Belete A, Alebachew T, Tsehaye H, Berhanu H, Minwuyelet A. 2017. Bacterial probiotics their importances and limitations: a review.
J. Nutr. Health Sci. 4 . DOI:10.15744/2393-9060.4.202. - Dudek-Wicher R, Junka A, Paleczny J, Bartoszewicz M. 2020. Clinical trials of probiotic strains in selected disease entities.
Int. J. Microbiol. 2020 : 8854119. - Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S,
et al . 2018. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features.Cell 174 : 1388-1405.e21. - Suez J, Zmora N, Segal E, Elinav E. 2019. The pros, cons, and many unknowns of probiotics.
Nat. Med. 25 : 716-729. - Boyer EW, Shannon M. 2005. The serotonin syndrome.
New Engl. J. Med. 352 : 1112-1120. - Lee YS, Lai DM, Huang HJ, Lee‐Chen G, Chang CH, Hsieh-Li HM,
et al . 2021. Prebiotic lactulose ameliorates the cognitive deficit in Alzheimer's disease mouse model through macroautophagy and chaperone-mediated autophagy pathways.J. Agric. Food Chem. 69 : 2422-2437.
Related articles in JMB

Article
Review
J. Microbiol. Biotechnol. 2024; 34(9): 1739-1747
Published online September 28, 2024 https://doi.org/10.4014/jmb.2403.03021
Copyright © The Korean Society for Microbiology and Biotechnology.
Using Synbiotics as a Therapy to Protect Mental Health in Alzheimer's Disease
Anh Pham Thi Ngoc1, Adil Zahoor1, Dong Gyun Kim1, and Seung Hwan Yang1*
Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea
Correspondence to:Seung Hwan Yang, ymichigan@jnu.ac.kr
Abstract
Alzheimer’s disease (AD) is a progressive neurological disorder that represents a major cause of dementia worldwide. Its pathogenesis involves multiple pathways, including the amyloid cascade, tau protein, oxidative stress, and metal ion dysregulation. Recent studies have suggested a critical link between changes in gut microbial diversity and the disruption of the gut–brain axis in AD. Previous studies primarily explored the potential benefits of probiotics and prebiotics in managing AD. However, studies have yet to fully describe a novel promising approach involving the use of synbiotics, which include a combination of active probiotics and new-generation prebiotics. Synbiotics show potential for mitigating the onset and progression of AD, thereby offering a holistic approach to address the multifaceted nature of AD. This review article primarily aims to gain further insights into the mechanisms of AD, specifically the intricate interaction between gut bacteria and the brain via the gut–brain axis. By understanding this relationship, we can identify potential targets for intervention and therapeutic strategies to combat AD effectively. This review also discusses substantial evidence supporting the role of synbiotics as a promising AD treatment that surpasses traditional probiotic or prebiotic interventions. We find that synbiotics may be used not only to address cognitive decline but also to reduce AD-related psychological burden, thus enhancing the overall quality of life of patients with AD.
Keywords: Alzheimer&rsquo,s disease, synbiotics, anxiety, gut-brain axis
Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative illness that impairs neurocognitive function and impedes mental capacity development [1]. In 2020, approximately 5.8 million individuals were diagnosed with AD in America. This disease initially manifests as mild memory loss and gradually progresses to the loss of conversational ability and responsiveness to the environment. It primarily affects the parts of the brain responsible for thought, memory, and language [2].
Understanding the pathophysiology of AD and developing effective therapeutics are multifaceted fields of study. The etiology of AD involves various factors, including mitochondrial dysfunction, oxidative stress (OS), lipid peroxidation, reactive oxygen species (ROS), and DNA/RNA/protein oxidation. The progression of AD is also influenced by disruptions in energy metabolism and calcium homeostasis, as well as neuroinflammation and neuronal death [3]. Verbal and visual memory deficiencies have been associated with psychiatric illnesses such as anxiety, which are also related to decreased hippocampal volume and function in AD [4, 5]. Anxiety is an early symptom of AD, and several studies have established the correlation between anxiety and AD pathology biomarkers [6]. Individuals experiencing anxiety have shown positive amyloid scans and mesial temporal entorhinal alterations, which include atrophy, hypometabolism, and presence of neurofibrillary tangles [7]. In the context of AD, anxiety is attributed to multifactorial causes, such as neurobiological factors and psychological influences, including cognitive deficits and external stresses [6].
The concept of a “synbiotic” was initially introduced by Gibson and Roberfroid [8] to denote a synergistic combination of probiotics and prebiotics. Synbiotics were developed to overcome potential challenges in the survival of probiotics in the intestinal system and achieve the beneficial qualities of probiotics and prebiotics. Consequently, a well-balanced combination of these elements in one product yields outcomes superior to the individual activities of probiotics or prebiotics alone [2]. In recent years, studies on neurodegenerative pathology have focused on prebiotic, probiotic, and synbiotic nutrition [9]. The concept of “psychobiotics” has also emerged, thereby highlighting the mental health benefits of probiotics. The consumption of psychobiotics positively affects the gut–brain-mediated nervous system through various mechanisms, including neuroendocrine, neuroimmunological, and enteric pathways [10]. These effects help improve the functioning of the gastrointestinal and central nervous systems [10]. Numerous preclinical studies and clinical trials on AD have demonstrated the beneficial effects of probiotics and prebiotics. However, few studies have explored the use of synbiotics for the treatment of AD and mental health.
This review aims to explore the potential pathways that could serve as targets for the treatment of AD and to elucidate the health-promoting benefits of synbiotics on mental health. It also addresses the limitations that should be further studied.
Hypotheses Describing the Fundamental Mechanisms Underlying AD
With the understanding of the molecular causes of AD, potential medications that can inhibit the progression of this debilitating condition have been developed. Several hypotheses, including the amyloid cascade, hyperphosphorylated tau protein, metal ion, cholinergic and OS hypotheses, have been proposed as fundamental mechanisms of AD (Fig. 1). In this section, we discuss these widely accepted concepts and explore clinical studies to evaluate their validity.
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Figure 1. Mechanisms underlying Alzheimer’s disease. It describes how synbiotics affects Alzheimer's disease through microbiota-gut-brain axis. The good probiotics could reduce inflammation, inhibit ROS, reduce the Aβ plaque formation and increase protective molecules such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Meanwhile, signals from the brain help stimulate the production of short-chain fatty acids (SCFAs), serotonin and reduce proinflammatory cytokines in the gut.
Amyloid Cascade Hypothesis
According to the amyloid cascade hypothesis, first proposed in 1991, the abnormal accumulation of amyloid β (Aβ) plaques in different brain regions contributes to neurodegeneration in AD. Aβ plaques act as triggers for a cascade of events, including neurotic damage [11], formation of neurofibrillary tangles through tau protein, neuronal dysfunction, and cell death [12]. This process stimulates microglia and astrocytes, resulting in inflammatory and oxidative responses. Ultimately, neuronal malfunction and apoptosis may lead to AD development (Fig. 2A).
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Figure 2. Pathogenesis of Alzheimer’s disease. (A) Amyloid beta (Aβ) cascade hypothesis; (B) hyperphosphorylated tau protein hypothesis; (C) metal ion hypothesis; and (D) oxidative stress hypothesis.
Aβ can activate tau protein kinase 1; consequently, it triggers the abnormal phosphorylation of tau protein and causes the formation of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs). Because of these pathological changes, the progression of tau pathology in AD further accelerates [13]. Furthermore, certain genetic factors considerably influence the onset and progression of AD [14]. Genes such as APP, PSEN-1, and PSEN-2 are strongly associated with AD pathology and can cause abnormal Aβ production [15]. Clinical research has devoted remarkable efforts to developing novel anti-AD drugs. Although approved medications provide symptomatic relief, they do not alter the disease course. These medications are often related to critical adverse effects and should only be used in severe cases. Therefore, ongoing research focuses on amyloid-based therapeutics to provide potentially effective treatments for this disease. Interventions based on the Aβ hypothesis aim to reduce Aβ production and aggregation while enhancing its clearance.
Hyperphosphorylated tau Protein Hypothesis
Tau protein is a family of six highly soluble protein isoforms encoded by the microtubule-associated protein tau gene. They preserve the stability of microtubules in axons and are widely distributed in neurons in the central nervous system (CNS). Conversely, they are less prevalent in oligodendrocytes and astrocytes, which are immune cells in the brain [16]. When tau undergoes atypical phosphorylation, normal adult tau is converted into PHF-tau. Then, these insoluble filaments accumulate and form NFTs, a characteristic hallmark of AD [17].
Various approaches have been explored to inhibit tau protein and consequently prevent neurodegenerative diseases, including AD. In one strategy, protein kinases are modified to prevent the abnormal hyperphosphorylation of tau. By targeting these kinases, researchers aim to maintain the normal phosphorylation state of tau and prevent neurofibrillary tangle formation. In another approach, anti-inflammatory treatments are used to alleviate brain inflammation, which has been implicated in tau hyperphosphorylation and aggregation (Fig. 2B) [18].
Metal ion Hypothesis
Metal ions, such as zinc and copper, participate in neuronal activity and the functioning of metalloproteins within synapses (Fig. 2C). These ions maintain normal brain cell function and synaptic transmission. However, disturbances in the homeostasis of metal ions or the accumulation of metals without known biological functions can disrupt the ionic balance and favor the development of neurodegenerative disorders, including AD [19].
The function of metal ions in AD has been elucidated for their use in potential therapeutic strategies. For example, the pathological effects associated with Aβ and tau protein aggregation may be mitigated by modulating metal ion concentrations or developing agents that can target metal ion imbalances. AD progression may be slowed down, and its debilitating effects may be alleviated by maintaining proper metal ion homeostasis and preventing metal-induced toxicity. However, further research and clinical investigations are needed to understand the complex relationship of metal ions with AD and to develop effective treatments targeting these mechanisms.
OS Hypothesis
OS is characterized by the accumulation of various compounds and free radicals derived from molecular oxygen. With aging, OS increases in the brain and causes a redox imbalance, which is attributed to the overproduction of ROS or a deficiency in the antioxidant system [20]. In the context of AD, OS is implicated in disease pathogenesis, triggering free radical production through processes such as dysfunction of the mitochondria and disruption of transition metal homeostasis (Fig. 2D). These free radicals lead to neurotoxicity mediated by Aβ and tau proteins [21].
OS has been implicated as a potential source of Aβ accumulation. In neuronal and non-neuronal cells, oxidants and oxidative byproducts can enhance the expression of amyloid precursor protein (APP) and increase the intracellular and released levels of Aβ [22]. Furthermore, Aβ promotes the release of endothelin-1 (ET-1), a peptide that binds to ETA receptors and reduces ROS levels. However, this binding leads to the release of calcium ions (Ca2+), thereby constricting pericytes and brain capillaries. Consequently, this constriction decreases the supply of glucose and oxygen in brain tissues and potentially contributes to the development of neuropsychiatric disorders [23]. Furthermore, the homeostasis of metals, including copper, zinc, and iron, can be disrupted by OS, and such disruption is closely linked to neural activity. These disturbances in metal homeostasis and abnormal interactions between Aβ and metal ions have been implicated in the development of Aβ deposition in the brains of individuals with AD. OS also considerably affect tau protein by promoting its hyperphosphorylation and polymerization [24]. Collectively, these findings suggest that reducing or eliminating ROS can potentially delay the onset or slow the progression of AD through various mechanisms. Natural antioxidants may help prevent or treat AD by targeting multiple distinct molecular mechanisms involved in the development and progression of AD.
Modulation of the Gut Microbiota–Brain Axis
The gut–brain axis (GBA) functions as a bidirectional communication system that connects the central and enteric neural systems and bridges the emotional and cognitive regions of the brain with peripheral functions of the intestine [25]. This axis preserves homeostasis in the digestive system, central nervous system, and gut microbiota [26]. Communication between the digestive system and the central brain involves various connections, including chemical mediators, neuronal networks, and the immune system [27].
The chemical communication between the gut microbiota and the nervous system is a critical aspect achieved through direct interactions involving short-chain fatty acids (SCFAs) and indirect chemical signaling pathways [27]. Numerous studies have emphasized that SCFAs influence the central nervous system by modulating neurotransmitter and neurotrophic factor levels. For instance, Schroeder
Studies on the equilibrium of innate immune system cells within the brain have shown that the bidirectional communication between the central nervous system and gut bacteria occurs through the immune pathway [30, 31]. Certain immune cells, such as T and B cells, considerably influence brain function. For instance, T cells are associated with various complex brain functions, including spatial working memory, cognition, emotion, and stress response [32], and B cells recruit peripheral immune cells to the injured brain [33]. The blood–brain barrier (BBB) limits the access of circulating T and B cells to the underlying parenchyma; as a result, immune modulation within the CNS is mediated by microglia, astrocytes, and oligodendrocytes [34]. The gut microbiome regulates and modifies the development and functioning of microglia [35]. Therefore, understanding the effect of the gut microbiota on the immune system and the CNS can provide valuable insights into potential therapeutic interventions for neurodegenerative diseases, including AD.
Synbiotics in Pharmaceutical Supplements for AD
Probiotics, which include bacteria that considerably affect human health, and prebiotics, which are fiber-based compounds that serve as nourishment for probiotics, can be combined to form synbiotics [36]. Well-known probiotic strains in the genus
In addition to the influence of probiotics, the effects of prebiotic components, such as fructooligosaccharides (FOS), which naturally occur in various fruits and vegetables, have been investigated in relation to cognitive deficits [40]. Chen
Xylooligosaccharides (XOS) have also been widely explored and have shown equally promising results. Han
Administering prebiotic and probiotic formulations in the diet of AD rats has favorable effects, including improved brain function caused by the reduction of gastrointestinal inflammation, OS in the hippocampus, and microglial activation [42]. Consequently, the combination of prebiotics and probiotics shows potential for enhancing the efficacy in reducing AD-related indicators.
Previous studies revealed that a high intake of prebiotics and probiotics, along with other nutrients, is associated with a slower cognitive decline and a reduced risk of AD [43]. Table 1 provides additional details regarding the diverse effects of synbiotic formulations.
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Table 1 . Effects of synbiotics on AD models..
Synbiotics Subject/Model Dose and duration Effects References In vitro experiments Lactobacillus plantarum ,Bifidobacterium infantis , andL. salivarius with grapeseed polyphenolic extractIn vitro model of the human gastrointestinal tract N/A ■ Inhibited the aggregation of amyloid plaques and tau fibrils
■ Exhibited anti-inflammatory activitiesPasinetti [44] In vivo experiments on mice L. plantarum 69-2 with GOSMale BALB/c mice aged 8 weeks were injected with 50 mg/ml Dgalactose per day for 6 weeks ■ 500 mg/kg GOS every day
■ 5×109 CFU kg/lL. plantarum 69-2 per day
■ Combination of 500 mg GOS and 5 × 109 CFUL. plantarum 69-2 daily■ Increased the total antioxidant capacity (T-AOC) and glutathione (GSH) activities, leading to enhanced antioxidant capacity in the liver
■ Decreased the amount ofProteobacteria in the stomach and considerably increased the quantity ofVerrucomicrobia and the levels of SCFA (acetate, propionate, and butyrate)
■ Repressed the gene expression of AMP-activated protein kinases (AMPK1 and AMPK2) and sirtuin 1 (SIRT1) and significantly increased the levels of aging-related genes, such as Bax, P53, and nuclear factor kappa-B (NF-κB), which might be attributed to the promotion of the AMPK/SIRT1 pathway, potentially regulating the expression of aging-related genesWang et al . [45]L. plantarum NCIMB 8826,Lactobacillus fermentum NCIMB 5221, andBifidobacterium longum spp.infantis withEmblica officinalis ,Terminalia bellirica , andTerminalia chebula powderDrosophila melanogaster with transgenic BACE1-APP gene■ 3.0 × 109 CFU/ml of each type of bacteria mixed with 0.5% of TFLA powder for 30 days ■ Slowed down acetylcholinesterase growth and improved survival
■ Inhibited the development of the pathogensS. aureus andE. coli
■ Increased the amount of total triglycerides because of the increased gene expression of acetyl CoA carboxylase after 30 days
■ Decreased the expression of lipid peroxidationWestfall et al . [46]Lactobacillus paracasei HII01 with XOSMale Wistar rats fed with a high-fat diet or normal diet ■ 2 ml of the combination of 10% XOS and 108 CFU L. paracasei HII01 for 12 weeks■ Reduced the mRNA expression levels of the proinflammatory cytokines interleukin (IL)-1 and IL-6
■ Prevented hippocampal dysplasia via LTP development and enhanced the dendritic spine density
■ Improved brain mitochondrial dysfunction, reduced hippocampus oxidative stress, and elicited anti-apoptotic effectsChunchai et al . [47]Lactobacillus rhamnosus UBLR-58 with curcuminMice with scopolamineinduced memory impairment ■ 1 ml/kg/day for 10 days ■ Increased antioxidant enzyme levels
■Minimized neuronal damage
■ Improved memory and cognitive functions in the behavioral studyPatel et al . [48]Prebiotics mixed with Vitalon Probiotics powder (v/v: 7/1) APP transgenic mice ■ 4.1 g/kg/day for 2months ■ Decreased the accumulation level of Aβ42
■ Did not change Aβ40
■ Reduced the TNF-α gene expression but did not affect IL-1βDeng et al . [49]In vivo experiments on humans Lactobacillus acidophilus ,Bifidobacterium bifidum , andB. longum with seleniumPatients with AD ■ 200 μg/day for 12 weeks ■ Improved cognitive function
■ Influenced the MMSE score, hs-CRP, TAC, GSH, insulin metabolism markers, triglycerides, VLDL-, LDL-, and total-/HDL-cholesterol
■ Improved the gene expression of TNF-a, PPAR-g, and LDLRTamtaji et al . [50]Milk supplemented with kefir grains Human ■ 2 ml per kilogram of body weight every day for 90 days ■ Favored cognitive improvement in the memory, language, construction ability, and attentional function assessments of patients after 90 days
■ Decreased the levels of O2-, H2O2, and ONOO-/OH- levels and increased the levels of NO and the oxidation–reduction of proteinsTon et al . [51]Lactobacillus acidophilus T16,B. bifidum BIA-6,Bifidobacterium lactis BIA-7, andB. longum BIA with maltodextrinPatients with high depression ■ 5 g of probiotics, 5 g of synbiotics, and 20 g of prebiotics in for weeks ■ Significantly increased the brain-derived neurotrophic factor in the synbiotic group compared with that in the probiotic and maltodextrin-only groups Haghighat et al . [52]
Prevention of AD by Neuroinflammation
The relationship between cytokines and AD has been established [43]. According to the amyloid cascade hypothesis, Aβ activates microglia and inflammatory cytokines [54]. In the prodromal phase of AD, soluble Aβ oligomers can decrease synaptic plasticity, impede potentiation, and stimulate microglia [55]. Neuroinflammation and pro-inflammatory cytokines enhance tau phosphorylation and decrease synaptic concentrations; consequently, cellular instability and neuronal death occur [56]. Aβ stimulates microglial receptors, which cause the release of cytokines, chemokines, and reactive oxygen species [57]. Additionally, when Aβ binds to the receptor for advanced glycation end products, inflammation occurs, and the release of pro-inflammatory cytokines such as TNFα and IL-6 is promoted [58]. Hence, the administration of anti-inflammatories can be a promising technique to prevent the incidence and progression of AD. The cytokine balance has been a focal point in understanding the etiology of AD and identifying potential new treatment targets. As illustrated in Table 1, the consumption of kefir-fermented milk considerably reduces systemic inflammation mediated by pro-inflammatory cytokines, such as IL-8, IL-12, and TNF-α [51]. TNF-α particularly participates in the inflammatory cascade and exacerbates the Aβ and tau pathology in patients with AD [59]. Short-term anti-TNF-α therapy can reduce pathology and improve cognition in these patients [60]. Similarly, the neurogenesis levels of Aβ42 in APP mice fed with only the combination of prebiotics and Vitalon Probiotics powder decrease compared with those in prebiotic-treated and control mice [49]. TNF-α levels are also reduced, but IL-1β levels remain unchanged [49].
The increased levels of the p40 subunit of IL-12 have been associated with the onset of AD [61]. Conversely, the decreased levels of IL-12 and p40 may mitigate cognitive decline and AD-related pathologies [62]. Kefir milk supplementation causes a decrease in pro-inflammatory activity and simultaneously balances pro- and anti-inflammatory cytokine levels [51]. Furthermore, IL-1β and IL-6 have been implicated in AD risk [54]. IL-1β overexpression inhibits the activity of the cholinergic system and promotes the accumulation of Aβ and NFT in AD [63]. Excessive IL-6 influences the cdk5/p53 pathway, thereby triggering tau phosphorylation [57]. Wang
Prevention of AD via OS
Serum levels of OS biomarkers are increased in patients with neurodegenerative disorders; as such, they can be used to evaluate the effectiveness of novel therapeutic approaches for patients with AD [67]. ROS plays direct and indirect roles in the pathophysiology of AD. For instance, increased levels of free radicals, such as O2, H2O2, and NO, can damage proteins, lipids, and nucleic acids; consequently, mitochondrial degeneration and neurotoxicity occur [68]. Additionally, OS is related to Aβ-induced neurodegeneration in patients with AD [69]. BDNF serum levels are also closely correlated with AD. BDNF is an endogenous protein involved in brain function, synaptic plasticity, and structural integrity [70]. A reduced BDNF level is considered a hallmark of AD; therefore, BDNF is considered an important pathway in AD treatment [71]. In a 12-week randomized clinical trial, Haghighat et al. [52] compared the effects of consuming synbiotic supplementation with
Kefir treatment considerably reduces protein oxidation. Notably, kefir supplementation also decreases blood ROS availability and increases NO levels, indicating that plasma protein oxidation is reduced in patients with AD. Chunchai
Prevention of AD by SCFAs and Other Substances
SCFAs play a crucial role in controlling neuroinflammatory processes implicated in dementia disorders, including AD. They participate in energy metabolism and thus help compensate for any metabolic deficiencies in the brain [72]. Yilmaz
Westfall
Depression is considered an early symptom and risk factor for AD diagnosis. Individuals who have experienced depressive episodes in the past more likely develop AD later in life compared with those without a history of depression [79]. This observation highlights the importance of mental health in the context of neurological disorders. Furthermore, changes in the gut microbiota have been associated with variations in the progression of neurodegenerative diseases, including AD [80]. Tamtaji
Future Concerns about Synbiotics for the Prevention of AD
Synbiotic medication shows therapeutic potential for AD; however, several limitations should be addressed before it can be recommended in medical practice. First, consuming probiotics has raised concerns on its potential adverse effects, including sepsis, hypersensitivity reactions, and gene transfer leading to pathogenic antibiotic resistance [81]. Another study specifically warns against the use of probiotics in patients with AD receiving immunosuppressive therapies such as chemotherapy because of cases of fungal blood infections and sepsis in recipients of
Second, the effects of probiotics exhibit individual variability [83]. Because of this variability, determining which specific probiotic within a multi-probiotic treatment is responsible for observed outcomes becomes challenging. Some studies have suggested that using probiotics after antibiotic treatment can increase the risk of contracting infectious diseases by causing persistent dysbiosis [84]. Probiotics can metabolize tryptophan, which substantially raises the risk of serotonin syndrome in combination with potent selective serotonin reuptake inhibitors [41]. The effects of serotonin syndrome can range from mild symptoms, such as shivering and diarrhea, to severe manifestations, including muscle rigidity, fever, seizures, and even death [85]. Therefore, a limited number of studies have investigated the application of probiotics and synbiotics as a medical intervention for AD. Extreme caution should be exercised when considering their use in humans, particularly in the elderly and individuals with multiple comorbidities.
Lastly, the potential negative effects of prebiotics on AD have not been extensively studied. However, certain prebiotics may contribute to neuroinflammation. For example, lactulose, a prebiotic, is associated with reduced short-term memory and impaired learning capacity in mice with AD [86]. To address these concerns and mitigate potential risks, researchers should conduct further long-term studies on the mechanisms, benefits, and drawbacks of synbiotics. Obtaining additional evidence supporting their safety and efficacy will enhance their reliability and maximize their potential for pharmaceutical and medical applications to prevent and manage AD.
Conclusion
Synbiotics have shown promising results in improving microbiome stability and surpassing the individual use of probiotics or prebiotics alone. They positively affect brain health, particularly the prevention of neurodegenerative diseases such as AD. They may mitigate or even reverse the primary symptoms of AD through various mechanistic pathways, such as reducing chronic neuroinflammation, modulating peripheral factors, influencing the production and translation of neurotoxic metabolites, regulating gut microbiota, and reducing OS. However, further studies should be performed to fully understand the etiology of AD and reveal the mechanisms by which synbiotics exert their effects.
The encouraging outcomes described in this review support the potential use of synbiotics as an effective medical therapy for AD. Nonetheless, further research is required to elucidate their precise mode of action and establish stronger connections between microbial and AD research. Continued investigation will help clarify their therapeutic mechanisms and optimize their application in AD prevention and treatment.
Conflict of Interest
The authors have no financial conflicts of interest to declare.
- Abstract
- Introduction
- Hypotheses Describing the Fundamental Mechanisms Underlying AD
- Amyloid Cascade Hypothesis
- Hyperphosphorylated tau Protein Hypothesis
- Metal ion Hypothesis
- OS Hypothesis
- Modulation of the Gut Microbiota–Brain Axis
- Synbiotics in Pharmaceutical Supplements for AD
- Prevention of AD by Neuroinflammation
- Prevention of AD via OS
- Prevention of AD by SCFAs and Other Substances
- Future Concerns about Synbiotics for the Prevention of AD
- Conclusion
- Conflict of Interest
Fig 1.

Fig 2.

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Table 1 . Effects of synbiotics on AD models..
Synbiotics Subject/Model Dose and duration Effects References In vitro experiments Lactobacillus plantarum ,Bifidobacterium infantis , andL. salivarius with grapeseed polyphenolic extractIn vitro model of the human gastrointestinal tract N/A ■ Inhibited the aggregation of amyloid plaques and tau fibrils
■ Exhibited anti-inflammatory activitiesPasinetti [44] In vivo experiments on mice L. plantarum 69-2 with GOSMale BALB/c mice aged 8 weeks were injected with 50 mg/ml Dgalactose per day for 6 weeks ■ 500 mg/kg GOS every day
■ 5×109 CFU kg/lL. plantarum 69-2 per day
■ Combination of 500 mg GOS and 5 × 109 CFUL. plantarum 69-2 daily■ Increased the total antioxidant capacity (T-AOC) and glutathione (GSH) activities, leading to enhanced antioxidant capacity in the liver
■ Decreased the amount ofProteobacteria in the stomach and considerably increased the quantity ofVerrucomicrobia and the levels of SCFA (acetate, propionate, and butyrate)
■ Repressed the gene expression of AMP-activated protein kinases (AMPK1 and AMPK2) and sirtuin 1 (SIRT1) and significantly increased the levels of aging-related genes, such as Bax, P53, and nuclear factor kappa-B (NF-κB), which might be attributed to the promotion of the AMPK/SIRT1 pathway, potentially regulating the expression of aging-related genesWang et al . [45]L. plantarum NCIMB 8826,Lactobacillus fermentum NCIMB 5221, andBifidobacterium longum spp.infantis withEmblica officinalis ,Terminalia bellirica , andTerminalia chebula powderDrosophila melanogaster with transgenic BACE1-APP gene■ 3.0 × 109 CFU/ml of each type of bacteria mixed with 0.5% of TFLA powder for 30 days ■ Slowed down acetylcholinesterase growth and improved survival
■ Inhibited the development of the pathogensS. aureus andE. coli
■ Increased the amount of total triglycerides because of the increased gene expression of acetyl CoA carboxylase after 30 days
■ Decreased the expression of lipid peroxidationWestfall et al . [46]Lactobacillus paracasei HII01 with XOSMale Wistar rats fed with a high-fat diet or normal diet ■ 2 ml of the combination of 10% XOS and 108 CFU L. paracasei HII01 for 12 weeks■ Reduced the mRNA expression levels of the proinflammatory cytokines interleukin (IL)-1 and IL-6
■ Prevented hippocampal dysplasia via LTP development and enhanced the dendritic spine density
■ Improved brain mitochondrial dysfunction, reduced hippocampus oxidative stress, and elicited anti-apoptotic effectsChunchai et al . [47]Lactobacillus rhamnosus UBLR-58 with curcuminMice with scopolamineinduced memory impairment ■ 1 ml/kg/day for 10 days ■ Increased antioxidant enzyme levels
■Minimized neuronal damage
■ Improved memory and cognitive functions in the behavioral studyPatel et al . [48]Prebiotics mixed with Vitalon Probiotics powder (v/v: 7/1) APP transgenic mice ■ 4.1 g/kg/day for 2months ■ Decreased the accumulation level of Aβ42
■ Did not change Aβ40
■ Reduced the TNF-α gene expression but did not affect IL-1βDeng et al . [49]In vivo experiments on humans Lactobacillus acidophilus ,Bifidobacterium bifidum , andB. longum with seleniumPatients with AD ■ 200 μg/day for 12 weeks ■ Improved cognitive function
■ Influenced the MMSE score, hs-CRP, TAC, GSH, insulin metabolism markers, triglycerides, VLDL-, LDL-, and total-/HDL-cholesterol
■ Improved the gene expression of TNF-a, PPAR-g, and LDLRTamtaji et al . [50]Milk supplemented with kefir grains Human ■ 2 ml per kilogram of body weight every day for 90 days ■ Favored cognitive improvement in the memory, language, construction ability, and attentional function assessments of patients after 90 days
■ Decreased the levels of O2-, H2O2, and ONOO-/OH- levels and increased the levels of NO and the oxidation–reduction of proteinsTon et al . [51]Lactobacillus acidophilus T16,B. bifidum BIA-6,Bifidobacterium lactis BIA-7, andB. longum BIA with maltodextrinPatients with high depression ■ 5 g of probiotics, 5 g of synbiotics, and 20 g of prebiotics in for weeks ■ Significantly increased the brain-derived neurotrophic factor in the synbiotic group compared with that in the probiotic and maltodextrin-only groups Haghighat et al . [52]
References
- Srivastava S, Ahmad R, Khare SK. 2021. Alzheimer's disease and its treatment by different approaches: a review.
Eur. J. Med. Chem. 216 : 113320. - Haghighat N, Mohammadshahi M, Shayanpour S, Haghighizadeh MH, Rahmdel S, Rajaei M. 2021. The effect of synbiotic and probiotic supplementation on mental health parameters in patients undergoing hemodialysis: a double-blind, randomized, placebocontrolled trial.
Indian J. Nephrol. 31 : 149. - Talebi M, Kakouri E, Talebi M, Tarantilis PA, Farkhondeh T, İlgün S,
et al . 2021. Nutraceuticals-based therapeutic approach: recent advances to combat pathogenesis of Alzheimer's disease.Exp. Rev. Neurother. 21 : 625-642. - DeCarolis NA, Eisch AJ. 2010. Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation.
Neuropharmacology 58 : 884-893. - Ravetz RS. 1999. Psychiatric disorders associated with Alzheimer's disease.
J. Am. Osteopath. Assoc. 99 : S13-16. - Mendez MF. 2021. The relationship between anxiety and Alzheimer's disease1.
J. Alzheimer's Disease Rep. 5 : 171-177. - Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT,
et al . 2021. Alzheimer disease.Nat. Rev. Dis. Primers 7 : 33. - Gibson GR, Probert HM, Van Loo J, Rastall RA, Roberfroid M. 2004. Dietary modulation of the human colonic microbiota: updating the concept of prebiotics.
Nutr. Res. Rev. 17 : 259-275. - Dinan TG, Stanton C, Cryan JF. 2013. Psychobiotics: a novel class of psychotropic.
Biol. Psychiatry 74 : 720-726. - Cheng L, Liu YW, Wu CC, Wang S, Tsai Y. 2019. Psychobiotics in mental health, neurodegenerative and neurodevelopmental disorders.
J. Food Drug Anal. 27 : 632-648. - Lustbader JW, Cirilli M, Lin C, Xu H, Takuma K, Wang N,
et al . 2004. ABAD directly links ASS to mitochondrial toxicity in Alzheimer's disease.Science 304 : 448-452. - Hunt D, Castillo PE. 2012. Synaptic plasticity of NMDA receptors: mechanisms and functional implications.
Curr. Opin. Neurobiol. 22 : 496-508. - Vergara C, Houben S, Suain V, Yilmaz Z, De Decker R, Vanden Dries V,
et al . 2019. Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo.Acta Neuropathol. 137 : 397-412. - Bertram L, Tanzi RE. 2008. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.
Nat. Rev. Neurosci. 9 : 768-778. - Shen J, Kelleher RJ. 2007. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism.
Proc. Natl. Acad. Sci. USA 104 : 403-409. - Michalicová A, Majerová P, Kováč A. 2020. TAU protein and its role in blood-brain barrier dysfunction.
Front. Mol. Neurosci. 13 : 570045. - Medeiros R, Baglietto‐Vargas D, LaFerla FM. 2011. The role of TAU in Alzheimer's disease and related disorders.
CNS Neurosci. Ther. 17 : 514-524. - Iqbal K, Liu F, Chen G, Grundke‐Iqbal I. 2010. Tau in Alzheimer disease and related tauopathies.
Curr. Alzheimer Res. 7 : 656-664. - Budimir A. 2011. Metal ions, Alzheimer's disease and chelation therapy.
Acta Pharm. 61 : 1-14. - Nita M, Grzybowski A. 2016. The role of the reactive oxygen species and oxidative stress in the pathomechanism of the Age-Related ocular diseases and other pathologies of the anterior and posterior eye segments in adults.
Oxid. Med. Cell. Longevity 2016 : 1-23. - Zhao Y, Zhao B. 2013. Oxidative stress and the pathogenesis of Alzheimer's disease.
Oxid. Med. Cell. Longev. 2013 : 1-10. - Guglielmotto. 2010. Oxidative stress mediates the pathogenic effect of different Alzheimer's disease risk factors.
Front. Aging Neurosci. : 10. doi: 10.3389/neuro.24.003.2010.eCollection 2010. - Fan L, Mao C, Hu X, Zhang S, Yang Z, Hu ZW,
et al . 2020. New insights into the pathogenesis of Alzheimer's disease.Front. Neurol. 10 : 1312. - Haque MdM, Murale DP, Kim YK, Lee JH. 2019. Crosstalk between oxidative stress and tauopathy.
Int. J. Mol. Sci. 20 : 1959. - Martin CR, Osadchiy V, Kalani A, Mayer EA. 2018. The brain-gut-microbiome axis.
Cell. Mol. Gastroenterol. Hepatol. 6 : 133-148. - Carabotti M, Scirocco A, Maselli MA, Severi C. 2015. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.
Ann. Gastroenterol. 28 : 203-209. - Morais LH, Schreiber HL, Mazmanian SK. 2020. The gut microbiota-brain axis in behaviour and brain disorders.
Nat. Rev. Microbiol. 19 : 241-255. - Schroeder FA, Lin CL, Crusio WE, Akbarian S. 2007. Antidepressant-Like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse.
Biol. Psych. 62 : 55-64. - Frost G, Sleeth M, Sahuri-Arisoylu M, Lizarbe B, Cerdán S, Brody L,
et al . 2014. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism.Nat. Commun. 5 : 3611. - Louveau A, Smirnov I, Keyes T, Eccles JD, Rouhani SJ, Peske JD,
et al . 2015. Structural and functional features of central nervous system lymphatic vessels.Nature 523 : 337-341. - Yoo BH, Mazmanian SK. 2017. The enteric network: interactions between the immune and nervous systems of the gut.
Immunity 46 : 910-926. - Morimoto K, Nakajima K. 2019. Role of the immune system in the development of the central nervous system.
Front. Neurosci. 13 : 916. - Ortega SB, Torres V, Latchney SE, Whoolery CW, Noorbhai I, Poinsatte K,
et al . 2020. B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice.Proc. Natl. Acad. Sci. USA 117 : 4983-4993. - Erny D, De Angelis ALH, Jaitin DA, Wieghofer P, Staszewski O, David E,
et al . 2015. Host microbiota constantly control maturation and function of microglia in the CNS.Nat. Neurosci. 18 : 965-977. - Mukherjee S, Joardar N, Sengupta S, Babu SPS. 2018. Gut microbes as future therapeutics in treating inflammatory and infectious diseases: lessons from recent findings.
J. Nutr. Biochem. 61 : 111-128. - Bonfili L, Cecarini V, Berardi S, Scarpona S, Suchodolski JS, Nasuti C,
et al . 2017. Microbiota modulation counteracts Alzheimer's disease progression influencing neuronal proteolysis and gut hormones plasma levels.Sci. Rep. 7 : 2426. - Archie SR, Shoyaib AA, Cucullo L. 2021. Blood-brain barrier dysfunction in CNS disorders and putative therapeutic targets: an overview.
Pharmaceutics 13 : 1779. - Kobayashi Y, Sugahara H, Shimada K, Mitsuyama E, Kuhara T, Yasuoka A,
et al . 2017. Therapeutic potential ofBifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer's disease.Sci. Rep. 7 : 13510. - Kobayashi Y, Kuhara T, Oki M, Xiao J. 2019. Effects of
Bifidobacterium breve A1 on the cognitive function of older adults with memory complaints: a randomised, double-blind, placebo-controlled trial.Benef. Microbes 10 : 511-520. - Han D, Li Z, Liu T, Yang N, Li Y, He J,
et al . 2020. Prebiotics regulation of intestinal microbiota attenuates cognitive dysfunction induced by surgery stimulation in APP/PS1 mice.Aging Dis. 11 : 1029. - Arora K, Green M, Prakash S. 2020. The microbiome and Alzheimer's disease: potential and limitations of prebiotic, synbiotic, and probiotic formulations.
Front. Bioeng. Biotechnol. 8 : 537847. - Pistollato F, Iglesias RC, Ruíz R, Aparicio S, Crespo J, López LAD,
et al . 2018. Nutritional patterns associated with the maintenance of neurocognitive functions and the risk of dementia and Alzheimer's disease: a focus on human studies.Pharmacol. Res. 131 : 32-43. - Chen D, Yang X, Yang J, Lai G, Yong T, Tang X,
et al . 2017. Prebiotic effect of fructooligosaccharides from morinda officinalis on Alzheimer's disease in rodent models by targeting the microbiota-gut-brain axis.Front. Aging Neurosci. 9 : 403. - Pasinetti GM. 2020. Synbiotic-derived metabolites reduce neuroinflammatory symptoms of Alzheimer's disease.
Curr. Dev. Nutr. 4 : nzaa062_035. - Wang W, Liu F, Xu C, Liu Z, Ma J, Gu L,
et al . 2021.Lactobacillus plantarum 69-2 Combined with galacto-oligosaccharides alleviates d-galactose-induced aging by regulating the AMPK/SIRT1 signaling pathway and gut microbiota in mice.J. Agric. Food Chem. 69 : 2745-2757. - Westfall S, Lomis N, Prakash S. 2019. A novel synbiotic delays Alzheimer's disease onset via combinatorial gut-brain-axis signaling in
Drosophila melanogaster .PLoS One 14 : e0214985. - Chunchai T, Thunapong W, Yasom S, Wanchai K, Eaimworawuthikul S, Metzler G,
et al . 2018. Decreased microglial activation through gut-brain axis by prebiotics, probiotics, or synbiotics effectively restored cognitive function in obese-insulin resistant rats.J. Neuroinflammation 15 : 11. - Patel C, Patel C, Acharya S. 2020. Potentiation of anti-Alzheimer activity of curcumin by probiotic
Lactobacillus rhamnosus UBLR-58 against scopolamine-induced memory impairment in mice.Naunyn-Schmiedeberg's Arch. Pharmacol. 393 : 1955-1962. - Deng S, Chen C, Lin H, Cheng IH. 2021. The beneficial effect of synbiotics consumption on Alzheimer's disease mouse model via reducing local and systemic inflammation.
IUBMB Life 74 : 748-753. - Tamtaji OR, Heidari‐Soureshjani R, Mirhosseini N, Kouchaki E, Bahmani F, Aghadavod E,
et al . 2019. Probiotic and selenium cosupplementation, and the effects on clinical, metabolic and genetic status in Alzheimer's disease: a randomized, double-blind, controlled trial.Clin. Nutr. 38 : 2569-2575. - Ton AMM, Campagnaro BP, Alves GA, Aires R, Côco LZ, Arpini CM,
et al . 2020. Oxidative stress and dementia in Alzheimer's patients: effects of synbiotic supplementation.Oxid. Med. Cell. Longev. 2020 : 2638703. - Haghighat N, Rajabi S, Mohammadshahi M. 2019. Effect of synbiotic and probiotic supplementation on serum brain-derived neurotrophic factor level, depression and anxiety symptoms in hemodialysis patients: a randomized, double-blinded, clinical trial.
Nutr. Neurosci. 24 : 490-499. - Su F, Bai F, Zhang Z. 2016. Inflammatory cytokines and Alzheimer's disease: a review from the perspective of genetic polymorphisms.
Neurosci. Bull. 32 : 469-480. - Garcez ML, Mina F, Bellettini-Santos T, Carneiro FG, Amparo L, Schiavo GL,
et al . 2017. Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid β (1-42) in mice.Prog. Neuropsychopharmacol. Biol. Psychiatry 77 : 23-31. - Selkoe DJ, Hardy J. 2016. The amyloid hypothesis of Alzheimer's disease at 25 years.
EMBO Mol. Med. 8 : 595-608. - Quintanilla RA, Orellana D, González-Billault C, Maccioni RB. 2004. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway.
Exper. Cell Res. 295 : 245-257. - Khoury JE, Moore KJ, Means TK, Leung JH, Terada K, Toft M,
et al . 2003. CD36 mediates the innate host response to Β-Amyloid.J. Exper. Med. 197 : 1657-1666. - Chellappa RC, Lukose B, Rani P. 2020. G82S RAGE polymorphism influences amyloid-RAGE interactions relevant in Alzheimer's disease pathology.
PLoS One 15 : e0225487. - Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S,
et al . 2008. Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTG-AD mice.Am. J. Pathol. 173 : 1768-1782. - McAlpine FE, Lee J, Harms AS, Ruhn KA, Blurton‐Jones M, Hong JJ,
et al . 2009. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology.Neurobiol. Dis. 34 : 163-177. - Berg JV, Prokop S, Miller KR, Obst J, Kälin RE, Lopategui-Cabezas I,
et al . 2012. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline.Nat. Med. 18 : 1812-1819. - Liu L, Xu Y, Liu Z, Chen JG, Zhang Y, Zhu J,
et al . 2011. IL12 polymorphisms, HBV infection and risk of hepatocellular carcinoma in a high‐risk Chinese population.Int. J. Cancer 128 : 1692-1696. - Halder N, Lal G. 2021. Cholinergic system and its therapeutic importance in inflammation and autoimmunity.
Front. Immunol. 12 : 660342. - Shah S, Yoon GH, Chung S, Abid MN, Kim TH, Lee HY,
et al . 2016. Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer's disease neuropathological deficits.Mol. Psychiatry 22 : 407-416. - Assefa BT, Tafere GG, Wondafrash DZ, Gidey MT. 2020. The bewildering effect of AMPK activators in Alzheimer's disease: review of the current evidence.
BioMed Res. Int. 2020 : 9895121. - Zhang M, Tang Z. 2023. Therapeutic potential of natural molecules against Alzheimer's disease via SIRT1 modulation.
Biomed. Pharmacother. 161 : 114474. - Manoharan S, Guillemin GJ, Abiramasundari RS, Essa MM, Akbar M. 2016. The role of reactive oxygen species in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease: a mini review.
Oxid. Med. Cell. Longev. 2016 : 8590578. - Oliver D, Reddy PH. 2019. Small molecules as therapeutic drugs for Alzheimer's disease.
Mol. Cell. Neurosci. 96 : 47-62. - Drake J, Link CD, Butterfield DA. 2003. Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid β-peptide (1-42) in a transgenic
Caenorhabditis elegans model.Neurobiol. Aging 24 : 415-420. - Laske C, Stransky E, Leyhe T, Eschweiler GW, Maetzler W, Wittorf A,
et al . 2007. BDNF serum and CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls.J. Psychiatr. Res. 41 : 387-394. - Mori Y, Tsuji M, Oguchi T, Kasuga K, Kimura A, Futamura A,
et al . 2021. Serum BDNF as a potential biomarker of Alzheimer's disease: verification through assessment of serum, cerebrospinal fluid, and medial temporal lobe atrophy.Front. Neurol. 12 : 653267. - Zilberter Y, Zilberter M. 2017. The vicious circle of hypometabolism in neurodegenerative diseases: ways and mechanisms of metabolic correction.
J. Neurosci. Res. 95 : 2217-2235. - Yılmaz A, Geddes TJ, Han B-S, Wilson GD, Imam K, Maddens M,
et al . 2017. Diagnostic biomarkers of Alzheimer's disease as identified in saliva using 1H NMR-based metabolomics.J. Alzheimer's disease 58 : 355-359. - Cui M, Jiang Y, Zhao Q, Zhu Z, Liang X, Zhang K,
et al . 2020. Metabolomics and incident dementia in older Chinese adults: the Shanghai aging study.Alzheimers Dement. 16 : 779-788. - Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti GM. 2017. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms.
Exp. Rev. Neurother. 18 : 83-90. - Fernando WMADB, Martins I, Morici M, Bharadwaj P, Rainey-Smith SR, Lim WLF,
et al . 2020. Sodium butyrate reduces brain amyloid-Β levels and improves cognitive memory performance in an Alzheimer's disease transgenic mouse model at an early disease stage.J. Alzheimer's Dis. 74 : 91-99. - Filippone A, Lanza M, Campolo M, Casili G, Paterniti I, Cuzzocrea S,
et al . 2020. Protective effect of sodium propionate in Aβ1-42 -induced neurotoxicity and spinal cord trauma.Neuropharmacology 166 : 107977. - Westfall S, Lomis N, Prakash S. 2018. A novel polyphenolic prebiotic and probiotic formulation have synergistic effects on the gut microbiota influencing
Drosophila melanogaster physiology.Artif. Cells Nanomed. Biotechnol. 46 : 441-455. - Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. 2006. Depression and risk for Alzheimer disease.
Arch. Gen. Psych. 63 : 530. - Methiwala HN, Vaidya B, Addanki VK, Bishnoi M, Sharma SS, Kondepudi KK. 2021. Gut microbiota in mental health and depression: role of pre/pro/synbiotics in their modulation.
Food Funct. 12 : 4284-4314. - Ayichew T, Belete A, Alebachew T, Tsehaye H, Berhanu H, Minwuyelet A. 2017. Bacterial probiotics their importances and limitations: a review.
J. Nutr. Health Sci. 4 . DOI:10.15744/2393-9060.4.202. - Dudek-Wicher R, Junka A, Paleczny J, Bartoszewicz M. 2020. Clinical trials of probiotic strains in selected disease entities.
Int. J. Microbiol. 2020 : 8854119. - Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S,
et al . 2018. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features.Cell 174 : 1388-1405.e21. - Suez J, Zmora N, Segal E, Elinav E. 2019. The pros, cons, and many unknowns of probiotics.
Nat. Med. 25 : 716-729. - Boyer EW, Shannon M. 2005. The serotonin syndrome.
New Engl. J. Med. 352 : 1112-1120. - Lee YS, Lai DM, Huang HJ, Lee‐Chen G, Chang CH, Hsieh-Li HM,
et al . 2021. Prebiotic lactulose ameliorates the cognitive deficit in Alzheimer's disease mouse model through macroautophagy and chaperone-mediated autophagy pathways.J. Agric. Food Chem. 69 : 2422-2437.