The Links Between the Gut Microbiome, Aging, Modern Lifestyle and Alzheimer's Disease

Askarova, Sholpan; Umbayev, Bauyrzhan; Masoud, Abdul-Razak; Kaiyrlykyzy, Aiym; Safarova, Yuliya; Tsoy, Andrey; Olzhayev, Farkhad; Kushugulova, Аlmagul

doi:10.3389/fcimb.2020.00104

Cited by 126 publications

(96 citation statements)

References 130 publications

(146 reference statements)

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“…Diabetes and Alzheimer’s disease share commonalities, including hyperglycemia, hyperinsulinemia, and memory impairment. Recent evidence has linked microbiome dysbiosis to be associated with neurological conditions including neuroinflammation and AD (Jiang et al, 2017 ; Cerovic et al, 2019 ; Askarova et al, 2020 ). In transgenic rodent models of AD, gut dysbiosis had positive correlations with AD pathology including cerebral amyloid-beta depositions (Cattaneo et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress

Govindarajulu

Pinky

Steinke

et al. 2020

Front. Mol. Neurosci.

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Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer’s model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an ex-vivo model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated ex-vivo slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress

Govindarajulu

Pinky

Steinke

et al. 2020

Front. Mol. Neurosci.

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“…Therefore, the gut microbiome plays a key role in maintaining the body healthy. So far, several review articles summarized well the role of gut microbiota in the maintenance of brain homeostasis (Fung et al, 2017 ; Tognini, 2017 ; Tremlett et al, 2017 ; Askarova et al, 2020 ). Here, we describe concisely the most important results about the role of gut microbiota in the regulation of brain physiological processes.…”

Section: The Gut Microbiome and Their Rolementioning

confidence: 99%

Target Dysbiosis of Gut Microbes as a Future Therapeutic Manipulation in Alzheimer’s Disease

Zhu

Chu

et al. 2020

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is commonly an age-associated dementia with neurodegeneration. The pathogenesis of AD is complex and still remains unclear. The inflammation, amyloid β (Aβ), and neurofibrillary tangles as well misfolded tau protein in the brain may contribute to the occurrence and development of AD. Compared with tau protein, Aβ is less toxic. So far, all efforts made in the treatments of AD with targeting these pathogenic factors were unsuccessful over the past decades. Recently, many studies demonstrated that changes of the intestinal environment and gut microbiota via gut–brain axis pathway can cause neurological disorders, such as AD, which may be involved in the pathogenesis of AD. Thus, remodeling the gut microbiota by various ways to maintain their balance might be a novel therapeutic strategy for AD. In the review article, we analyzed the characteristics of gut microbiota and its dysbiosis in AD and its animal models and investigated the possibility of targeting the gut microbiota in the treatment of the patients with AD in the future.

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“…An approach for slowing down the progress of the disease is targeting the factors that might accelerate neural damage. Present results suggest that unhealthy dietary habits, microbiota changes, and oxidative stress favor the development of brain insulin resistance, which could contribute to a neuroinflammatory profile, directly activating both the resident immune cells of the brain (microglia) and astrocytes, promoting an adverse environment for neuronal survival in the context of AD [ 3 , 4 ]. Accordingly, a more detailed in-depth analysis of central insulin resistance contribution to cognitive impairment is discussed later in this review.…”

Section: Introduction: Human Brain Aging and Inositolsmentioning

confidence: 99%

The Biomedical Uses of Inositols: A Nutraceutical Approach to Metabolic Dysfunction in Aging and Neurodegenerative Diseases

López-Gambero

Sanjuan²,

Serrano-Castro

et al. 2020

Biomedicines

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Inositols are sugar-like compounds that are widely distributed in nature and are a part of membrane molecules, participating as second messengers in several cell-signaling processes. Isolation and characterization of inositol phosphoglycans containing myo- or d-chiro-inositol have been milestones for understanding the physiological regulation of insulin signaling. Other functions of inositols have been derived from the existence of multiple stereoisomers, which may confer antioxidant properties. In the brain, fluctuation of inositols in extracellular and intracellular compartments regulates neuronal and glial activity. Myo-inositol imbalance is observed in psychiatric diseases and its use shows efficacy for treatment of depression, anxiety, and compulsive disorders. Epi- and scyllo-inositol isomers are capable of stabilizing non-toxic forms of β-amyloid proteins, which are characteristic of Alzheimer’s disease and cognitive dementia in Down’s syndrome, both associated with brain insulin resistance. However, uncertainties of the intrinsic mechanisms of inositols regarding their biology are still unsolved. This work presents a critical review of inositol actions on insulin signaling, oxidative stress, and endothelial dysfunction, and its potential for either preventing or delaying cognitive impairment in aging and neurodegenerative diseases. The biomedical uses of inositols may represent a paradigm in the industrial approach perspective, which has generated growing interest for two decades, accompanied by clinical trials for Alzheimer’s disease.

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The Links Between the Gut Microbiome, Aging, Modern Lifestyle and Alzheimer's Disease

Cited by 126 publications

References 130 publications

Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress

Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress

Target Dysbiosis of Gut Microbes as a Future Therapeutic Manipulation in Alzheimer’s Disease

The Biomedical Uses of Inositols: A Nutraceutical Approach to Metabolic Dysfunction in Aging and Neurodegenerative Diseases

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