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Murai, T.; Matsuda, S. Therapeutic Implications of Probiotics in Alzheimer’s Disease. Encyclopedia. Available online: (accessed on 18 June 2024).
Murai T, Matsuda S. Therapeutic Implications of Probiotics in Alzheimer’s Disease. Encyclopedia. Available at: Accessed June 18, 2024.
Murai, Toshiyuki, Satoru Matsuda. "Therapeutic Implications of Probiotics in Alzheimer’s Disease" Encyclopedia, (accessed June 18, 2024).
Murai, T., & Matsuda, S. (2023, July 04). Therapeutic Implications of Probiotics in Alzheimer’s Disease. In Encyclopedia.
Murai, Toshiyuki and Satoru Matsuda. "Therapeutic Implications of Probiotics in Alzheimer’s Disease." Encyclopedia. Web. 04 July, 2023.
Therapeutic Implications of Probiotics in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by the accumulation of specific proteins in the brain. Manipulating gut microbiota (GM) significantly reduced tau pathology and neurodegeneration in an apolipoprotein E isoform-dependent manner. The resilience of a healthy microbiota protects it from a variety of dysbiosis-related pathologies. Convincing evidence has demonstrated the roles of GM in the pathogenesis of AD, which are partly mediated by modified microglial activity in the brain. Therefore, modulation of GM may be a promising therapeutic option for AD prevention. 

gut microbiome probiotics Alzheimer’s Disease

1. Introduction

Neuroinflammation, such as microgliosis and astrogliosis, is one of the major hallmarks and pathological features associated with a wide variety of neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases [1]. The role of neuroinflammation in these neurodegenerative diseases is definitively demonstrated in prototypical neuroinflammatory diseases, such as multiple sclerosis, in addition to the invariable occurrence of inflammation in the brain. Among them, Alzheimer’s disease (AD) is the most common form of dementia, whose typical diagnostic feature is the increased deposition of neurofibrillary plaques in the brain. These insoluble protein aggregates mainly consisting of amyloid-β (Aβ) protein with an abnormal structure and hyper-phosphorylated tau proteins [1]. A pharmacological therapy effective in the treatment of AD by impeding the progression of the disease has not yet been established, and the only options available are restricted to symptomatic interventions that slow down the progression of the disease [1].

2. Oxidative Stress and Protein Aggregation in AD

One of the mechanisms confirmed in an experimental model of AD involves the reduction in oxidative damage-induced reactive oxygen species (ROS) [2]. ROS, as the name suggests, is a family of reactive species derived from molecular oxygen that are both continuously produced and scavenged in the cells of all aerobic organisms. Superoxide anion, hydroxyl radicals, alkoxyl radicals, and peroxyl radicals are the major free radical-type ROS, while hydrogen peroxide, ozone, singlet molecular oxygen, electronically excited carbonyls, and organic hydroperoxide are the major non-free radical forms of ROS. The excessive generation of ROS plays a critical role in the pathogenesis of diseases, and the improper regulation of ROS levels contributes to the pathologies of inflammation, cancer, and neurodegeneration. ROS are harmful to cell components and cause DNA damage [3]. Oxidative damage in cells is mainly attributed to the excess production of ROS. ROS produce metabolic intermediates that are involved in various signaling pathways. It has been reported that abnormal Aβ inhibited the long-term potentiation (LTP) in neurons that were saved with the administration of an antioxidant, suggesting a synergistic achievement between the progression of the pathogenesis of AD and oxidative stress [1]. Oxidative stress occurs and is a constant feature of AD brain pathology. Additionally, oxidative stress has a contributing role to neuroinflammation and the pathogenesis of AD [4]. ROS also act as secondary messengers in the transmission of redox-sensitive signals, including the stress-activated mitogen-activated protein kinases (MAPKs), p38 MAPKs, and c-Jun N-terminal kinases (JNKs). Thus, ROS has a dual function, with the other being to promote the activity of Akt. The Akt pathway can be induced through inhibition of the counteracting phosphatase and tensin homolog (PTEN). Events triggered via the phosphatidylinositol-3 kinase (PI3K) pathway involve the activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH) and the production of ROS. Thus, ROS are central to cellular redox regulation and exert positive feedback on the PI3K signaling pathway through mechanisms including the reversible oxidation and inactivation of PTEN and other phosphatases that negatively regulate this pathway.
AD is characterized by the accumulation of specific proteins in the brain. Aβ protein is accumulated in the extracellular space, and tau protein is accumulated as intracellular aggregates [5]. The only established biomarkers are Aβ (1–42), total tau, and phosphorylated tau in cerebrospinal fluid. The amyloid hypothesis proposes amyloid-β protein accumulation as the main cause of the disease. This protein is the main component of plaques and is derived from a longer type I membrane glycoprotein, amyloid precursor protein (APP). Aβ is a protein with 39 to 43 amino acid residues long originating from the C-terminal region of the APP by proteolytic processing. The cleavage of the APP by α-secretase releases a soluble APP-α from the cell surface and leaves an 83-amino-acid-long C-terminal APP fragment. The amyloidogenic processing of APP is executed through sequential cleavages by β- and γ-secretases at the N- and C-termini of Aβ, respectively. APP is produced in most peripheral cells, and Aβ is present in blood plasma in addition to the cerebrospinal fluid. There are two main isoforms of Aβ peptide in humans: Aβ (1–40) and Aβ (1–42); the former is more abundant, but the latter is able to form fibrils more rapidly and is considerably more neurotoxic. Aβ is predominantly expressed at the plasma membrane and transported to the extracellular space, where Aβ is deposited as protein deposits, called senile plaques, which are a characteristic feature of AD. The toxicity of Aβ is attributed to fibrillar Aβ, which is prone to damage neurons or initiate an intracellular signaling cascade toward neuronal cell death. Both isoforms are known to inhibit long-term potentiation (LTP) in neurons and support an enhancement of synaptic efficacy after brain high-frequency stimulation (HFS). Tau proteins are microtubule-associated proteins that are predominantly expressed in neurons. Tau-positive neurofibrillary lesions constitute mainly a neuropathological feature of AD. Although these proteins are considered hallmarks of the disease, brain atrophy only correlates highly with tau protein accumulation and not the deposition of Aβ protein [6]. The complex nature of the central nervous system (CNS) requires certain specialized immunological adaptations to detect and respond to environmental changes, and the local microenvironment in the brain related to tauopathy is often instructive for the recruitment and guidance of the transformation of T cells [7].

3. Gut Microbiota (GM) and Tauopathy

The maintenance of healthy GM is one of the important factors for the maintenance of the immune system and cognitive–emotional balance via the production of many biologically active metabolites, giving rise to the GM–brain axis [8]. The composition of GM generally exhibits a high variation among individuals, and once the diversity of the commensal microbiota is established to some extent during childhood, it exhibits strong resilience, i.e., its composition and activity subsequently remain substantially stable. This resilience of the health-promoting microbiota protects the host from a variety of pathologies related to dysbiosis [8]. Thus, interventions targeting them might be promising strategies for treating diseases and promoting health.
GM is reported to be closely related to a variety of cancers and neurological disorders. Intestinal dysbiosis also favors the growth of certain species of gut bacteria, which increases the risk of certain types of cancer through numerous mechanisms, including the production of many kinds of biological factors that degrade the products of tumor suppressor genes, the generation of oxidative stress, the activation of proinflammatory mechanisms, the alteration of cell proliferation, the modulation of survival pathways, and the alteration of the immune system [9]. Because of its influence on disease development and prognosis, the microbiota has become a target in the field of therapy [10].
The most well-known biological marker of neurodegeneration is the accumulation of misfolded and aggregated proteins in the brain [11]. These aggregates are often surrounded by certain immune cells, including microglia and astrocytes [12]. Patients with neurodegenerative disorders such as AD, Parkinson’s disease, and amyotrophic lateral sclerosis commonly exhibit alterations in their immune systems and the profile of the bacterial communities that inhabit their guts. GM can regulate gene expression in microglia in a manner correlated with the status of apolipoprotein E [12]. The apolipoprotein E ε4 allele mapped to chromosome 19q13.2 is the first gene to be identified and associated with a significantly enhanced risk of sporadic late-onset AD [13]. However, it is not clear whether the disruption of GM is a cause or a result of neurodegeneration or whether the timely treatment of this gut dysbiosis could impede its progress [13].
The role of GM in the pathogenesis of AD, which is partially mediated by altered microglial activity in the brain, has been demonstrated by compelling evidence [14]. In fact, microglial dysfunction has been detected in a variety of neurodegenerative disorders, including AD. The GM–glia–brain-immune axis might be influenced by the production of inflammatory cytokines and/or the reduction in the levels of certain metabolite compounds, such as SCFAs, thus modulating the regulation of the sympathetic afferent nerve and glial cells [14]. For example, butyric acid, being a key SCFA, might be associated with a favorable response in the treatment of schizophrenia, suggesting a pivotal role in the GM–brain axis [14]. Prebiotics are specific types of plant fibers that may stimulate the growth of healthy bacteria in the gut, while probiotics usually contain specific species of microorganisms that directly promote the growth of health-beneficial microbes in the gut [14].
GM could play a crucial role in promoting human health and ameliorating various diseases [15]. While Bacteroides sp. and Pseudomonas sp. can induce colitis, certain bacterial species may enhance the development of a good GM that helps in the inhibition of carcinogenesis [15]. The preliminary result implying that a specific type of probiotics can exhibit suppressive effects against inflammatory bowel disease-related carcinogenesis [15]. This might provide definitive evidence that probiotics consisting of specific strains of bacteria could prevent the development and inhibit the progression of inflammatory bowel disease-related tumors [15].
Microbe-derived metabolites not only provide cells with a source of energy and affect microglial maturation, they might also have the ability to influence neuronal function. SCFAs may modulate the levels of secretory neurotransmitter molecules and neurotrophic factors. For instance, acetate has previously been shown to alter the levels of neurotransmitter release including glutamate, glutamine, and γ-amino butyric acid (GABA) in the hypothalamus and increase neuropeptide expression [14]. Propionate and butyrate, the major SCFAs other than butylate, exert a distinct influence on the intracellular potassium ion level, implying the involvement of SCFAs in the modulation of cell signaling systems [14]. Time-dependent eating restrictions, which limit the daily timing for meals to a window of 6–12 h, have been shown to reduce the risks of cardiometabolic diseas

4. Identification of Possible Probiotics for the Treatment of AD

The potential approaches to practical therapeutic intervention for the improvement of microbiota-related diseases might target GM and/or their metabolites by following the alteration of pathological pathways in diseases [15]. One of these approaches may involve the utilization of pathways in the progression of diseases [15], while another may involve the utilization of probiotics.
Human GM and its metabolites also serve as potential targets for the development of therapeutic interventions for the prevention of such disorders. SCFAs are carboxylic acids containing fewer than six C atoms, such as acetic acid (CH3COOH), propionic acid (CH3CH2COOH), and butyric acid (CH3CH2 CH2COOH), are produced by GM, mainly through fermentation [16]. For example, a probiotic formulation of lactic acid bacteria and bifidobacteria (SLAB51) administration exerts multiple effects by modulating gut microbiota composition and causing metabolic changes, such as the increase in SCFAs, which are able to directly act in the gut and the brain due to their ability to pass the blood–brain barrier [17]. Recently, engineered probiotics have demonstrated their potential applicability as a novel type of drug delivery system that could effectively prevent inflammatory diseases [15]. These results further support the rational manufacturing of new types of probiotics for the targeted treatment of disorders [15]. Particularly, the anti-inflammatory molecules identified in preclinical and clinical studies may be of pivotal importance in providing insights into the identification of novel therapeutic targets for the practical application of genetically engineered probiotics [15]. In addition, engineered probiotics could serve as optimal vectors to safely produce beneficial biomolecules that are able to target specific endogenous molecules or specific xenobiotic pathogens [15]. The development of gene editing methods, such as clustered regularly interspaced palindromic repeat-associated proteins, is a breakthrough in the field of engineering. Utilizing such genome editing tools, probiotics are emerging and expanding their applicability to treat diseases and contribute to human health [15]. Further, synbiotics and postbiotics might also be applicable to treat AD by modulating GM.
A report that showed a high prevalence of Helicobacter pylori infection in patients with AD suggested that therapeutic eradication of this bacterium may improve the degenerative process in AD [16]. Another study revealed the possible neuroprotective effect of cycloserine against aluminum chloride-induced AD in rats [18]. Administration of aluminum chloride caused oxidative damage and neurodegeneration compared to the control group, and it was found that aluminum chloride decreased α-secretase activity while increasing the activities of both β-secretase and γ-secretase. On the other hand, cycloserine application improved the degree of neurodegeneration and oxidative damage caused by aluminum toxicity. It is believed that the results of this study will contribute to the synthesis of novel drugs with improved potential against neurodegeneration caused by aluminum, cognitive impairment, and medicinal development research [18]. Moreover, it has been reported that the consumption of a mixture of probiotics could affect cognitive function and some metabolic statuses in AD patients [19].
It is still unknown whether the manipulation of GM in the therapeutic application for AD can be achieved by using antibiotics or probiotics. The actions of antibiotics could be wide-ranging and even have the opposite effect, depending on the type of antibiotic used and the specific role of the microbiome in the pathogenesis of AD. Recently, it has been reported that the long-term treatment of an established antibiotic cocktail, ABX, containing kanamycin, gentamicin, colistin, metronidazole, and vancomycin, resulted in reduced Aβ deposition only in the aggressive male APPSWE/PS1L166P (APPPS1-21) mouse model of Aβ amyloidosis [20].


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