Retinoic Acid and the Gut Microbiota in Alzheimer’s Disease: Fighting Back-to-Back?

2019 ◽  
Vol 16 (5) ◽  
pp. 405-417 ◽  
Author(s):  
Kristina Endres
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Retinoic Acid ◽  
Gut Microbiota ◽  
Disease Risk ◽  
Current Knowledge ◽  
Retinoid Signaling ◽  
Retinoid Metabolism ◽  
Organ Systems ◽  
The Brain

Background: There is growing evidence that the gut microbiota may play an important role in neurodegenerative diseases such as Alzheimer’s disease. However, how these commensals influence disease risk and progression still has to be deciphered. Objective: The objective of this review was to summarize current knowledge on the interplay between gut microbiota and retinoic acid. The latter one represents one of the important micronutrients, which have been correlated to Alzheimer’s disease and are used in initial therapeutic intervention studies. Methods: A selective overview of the literature is given with the focus on the function of retinoic acid in the healthy and diseased brain, its metabolism in the gut, and the potential influence that the bioactive ligand may have on microbiota, gut physiology and, Alzheimer’s disease. Results: Retinoic acid can influence neuronal functionality by means of plasticity but also by neurogenesis and modulating proteostasis. Impaired retinoid-signaling, therefore, might contribute to the development of diseases in the brain. Despite its rather direct impact, retinoic acid also influences other organ systems such as gut by regulating the residing immune cells but also factors such as permeability or commensal microbiota. These in turn can also interfere with retinoid-metabolism and via the gutbrain- axis furthermore with Alzheimer’s disease pathology within the brain. Conclusion: Potentially, it is yet too early to conclude from the few reports on changed microbiota in Alzheimer’s disease to a dysfunctional role in retinoid-signaling. However, there are several routes how microbial commensals might affect and might be affected by vitamin A and its derivatives.

scholarly journals Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment

2020 ◽  
Vol 57 (12) ◽  
pp. 5026-5043 ◽  
Author(s):  
Shan Liu ◽  
Jiguo Gao ◽  
Mingqin Zhu ◽  
Kangding Liu ◽  
Hong-Liang Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Gut Dysbiosis ◽  
Bidirectional Communication ◽  
Significant Research ◽  
Novel Therapeutic Strategies ◽  
The Brain ◽  
Brain Homeostasis ◽  
Gut Microbiota Composition

Abstract Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term “microbiota-gut-brain axis” from “gut-brain axis” underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer’s disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.

scholarly journals Genetic Variants of Lipoprotein Lipase and Regulatory Factors Associated with Alzheimer’s Disease Risk

2020 ◽  
Vol 21 (21) ◽  
pp. 8338
Author(s):  
Kimberley D. Bruce ◽  
Maoping Tang ◽  
Philip Reigan ◽  
Robert H. Eckel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipoprotein Lipase ◽  
Genetic Variants ◽  
Disease Risk ◽  
Lipoprotein Metabolism ◽  
Protective Role ◽  
Direct Role ◽  
The Brain

Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer’s disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, HindIII, and PvuII) have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis.

scholarly journals Relationship between Wine Consumption, Diet and Microbiome Modulation in Alzheimer’s Disease

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3082
Author(s):  
M. Victoria Moreno-Arribas ◽  
Begoña Bartolomé ◽  
José L. Peñalvo ◽  
Patricia Pérez-Matute ◽  
Maria José Motilva
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Intestinal Microbiome ◽  
Dietary Polyphenols ◽  
Age Related ◽  
Wine Polyphenols ◽  
The Impact

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to the most common form of dementia in elderly people. Modifiable dietary and lifestyle factors could either accelerate or ameliorate the aging process and the risk of developing AD and other age-related morbidities. Emerging evidence also reports a potential link between oral and gut microbiota alterations and AD. Dietary polyphenols, in particular wine polyphenols, are a major diver of oral and gut microbiota composition and function. Consequently, wine polyphenols health effects, mediated as a function of the individual’s oral and gut microbiome are considered one of the recent greatest challenges in the field of neurodegenerative diseases as a promising strategy to prevent or slow down AD progression. This review highlights current knowledge on the link of oral and intestinal microbiome and the interaction between wine polyphenols and microbiota in the context of AD. Furthermore, the extent to which mechanisms bacteria and polyphenols and its microbial metabolites exert their action on communication pathways between the brain and the microbiota, as well as the impact of the molecular mediators to these interactions on AD patients, are described.

scholarly journals Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

2020 ◽  
Vol 21 (22) ◽  
pp. 8767
Author(s):  
Nicole Jacqueline Jensen ◽  
Helena Zander Wodschow ◽  
Malin Nilsson ◽  
Jørgen Rungby
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Brain Metabolism ◽  
Ketone Bodies ◽  
Current Knowledge ◽  
Ketogenic Diets ◽  
Cognitive Benefits ◽  
The Brain

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

scholarly journals The Presence of Human Herpesvirus 6 in the Brain in Health and Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1520
Author(s):  
Gabriel Santpere ◽  
Marco Telford ◽  
Pol Andrés-Benito ◽  
Arcadi Navarro ◽  
Isidre Ferrer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Current Knowledge ◽  
Human Herpesvirus ◽  
Brain Regions ◽  
Specific Cell ◽  
Human Herpesvirus 6 ◽  
Detection Techniques ◽  
Herpesvirus 6 ◽  
The Brain

The human herpesvirus 6 (HHV‐6) ‐A and ‐B are two dsDNA beta‐herpesviruses infectingalmost the entire worldwide population. These viruses have been implicated in multipleneurological conditions in individuals of various ages and immunological status, includingencephalitis, epilepsy, and febrile seizures. HHV‐6s have also been suggested as playing a role inthe etiology of neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease. Theapparent robustness of these suggested associations is contingent on the accuracy of HHV‐6detection in the nervous system. The effort of more than three decades of researching HHV‐6 in thebrain has yielded numerous observations, albeit using variable technical approaches in terms oftissue preservation, detection techniques, sample sizes, brain regions, and comorbidities. In thisreview, we aimed to summarize current knowledge about the entry routes and direct presence ofHHV‐6 in the brain parenchyma at the level of DNA, RNA, proteins, and specific cell types, inhealthy subjects and in those with neurological conditions. We also discuss recent findings relatedto the presence of HHV‐6 in the brains of patients with Alzheimer’s disease in light of availableevidence.

scholarly journals Alzheimer's Disease Risk Gene, GAB2, is Associated with Regional Brain Volume Differences in 755 Young Healthy Twins

2012 ◽  
Vol 15 (3) ◽  
pp. 286-295 ◽  
Author(s):  
Derrek P. Hibar ◽  
Neda Jahanshad ◽  
Jason L. Stein ◽  
Omid Kohannim ◽  
Arthur W. Toga ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Young Adult ◽  
Disease Risk ◽  
Adult Brain ◽  
Brain Morphology ◽  
Control Analysis ◽  
Risk Gene ◽  
Increased Risk ◽  
The Brain

The development of late-onset Alzheimer's disease (LOAD) is under strong genetic control and there is great interest in the genetic variants that confer increased risk. The Alzheimer's disease risk gene, growth factor receptor bound protein 2-associated protein (GAB2), has been shown to provide a 1.27–1.51 increased odds of developing LOAD for rs7101429 major allele carriers, in case-control analysis. GAB2 is expressed across the brain throughout life, and its role in LOAD pathology is well understood. Recent studies have begun to examine the effect of genetic variation in the GAB2 gene on differences in the brain. However, the effect of GAB2 on the young adult brain has yet to be considered. Here we found a significant association between the GAB2 gene and morphological brain differences in 755 young adult twins (469 females) (M = 23.1, SD = 3.1 years), using a gene-based test with principal components regression (PCReg). Detectable differences in brain morphology are therefore associated with variation in the GAB2 gene, even in young adults, long before the typical age of onset of Alzheimer's disease.

Gut Microbiota and Alzheimer’s Disease: Experimental Evidence and Clinical Reality

2021 ◽  
Vol 18 ◽  
Author(s):  
Sarama Saha ◽  
Sukhpal Singh ◽  
Suvarna Prasad ◽  
Amit Mittal ◽  
Anil Kumar Sharma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Experimental Evidence ◽  
Molecular Mechanisms ◽  
Bacterial Flora ◽  
Experimental Studies ◽  
The Elderly ◽  
The Impact ◽  
The Brain

: Alzheimer’s disease (AD) is characterized by progressive death of neuronal cells in the regions of the brain concerned with memory and cognition, and is the major cause of dementia in the elderly population. Various molecular mechanisms, metabolic risk factors and environmental triggers contributing to the genesis and progression of AD are under intense investigations. The present review has dealt with the impact of a highly discussed topic of gut microbiota affecting the neurodegeneration in the AD brain. A detailed description of the composition of gut bacterial flora and its interaction with the host has been presented, followed by an analysis of key concepts of bi- directional communication between gut microbiota and the brain. The substantial experimental evidence of gut microbiota affecting the neurodegenerative process in experimental AD models has been described next in this review, and finally, the limitations of such experimental studies vis-a- vis the actual disease and the paucity of clinical data on this topic have also been mentioned.

Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models

2015 ◽  
Vol 36 (2) ◽  
pp. 1221.e15-1221.e28 ◽  
Author(s):  
Henna Martiskainen ◽  
Jayashree Viswanathan ◽  
Niko-Petteri Nykänen ◽  
Mitja Kurki ◽  
Seppo Helisalmi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
In Vitro Models ◽  
Risk Genes ◽  
The Brain

scholarly journals Microglia Heterogeneity in Alzheimer’s Disease: Insights From Single-Cell Technologies

2021 ◽  
Vol 13 ◽  
Author(s):  
Hansen Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Cell ◽  
Current Knowledge ◽  
Cell Mass ◽  
Risk Genes ◽  
Functional Studies ◽  
Cell Technologies ◽  
The Central Nervous System ◽  
The Brain

Microglia are resident immune cells in the central nervous system and play critical roles in brain immunity, development, and homeostasis. The pathology of Alzheimer’s disease (AD) triggers activation of microglia. Microglia express many AD risk genes, suggesting that their response to AD pathology can affect disease progression. Microglia have long been considered a homogenous cell population. The diversity of microglia has gained great interest in recent years due to the emergence of novel single-cell technologies, such as single-cell/nucleus RNA sequencing and single-cell mass cytometry by time-of-flight. This review summarizes the current knowledge about the diversity/heterogeneity of microglia and distinct microglia states in the brain of both AD mouse models and patients, as revealed by single-cell technologies. It also discusses the future developments for application of single-cell technologies and the integration of these technologies with functional studies to further dissect microglia biology in AD. Defining the functional correlates of distinct microglia states will shed new light on the pathological roles of microglia and might uncover new relevant therapeutic targets for AD.

scholarly journals The Oral-Gut-Brain AXIS: The Influence of Microbes in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Narengaowa ◽  
Wei Kong ◽  
Fei Lan ◽  
Umer Farooq Awan ◽  
Hong Qing ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Neurofibrillary Tangles ◽  
Neurodegenerative Disorders ◽  
Cranial Nerves ◽  
Neuronal Necrosis ◽  
Fundamental Causes ◽  
Oral Microbes ◽  
The Brain

Alzheimer’s disease (AD) is one of the most frequently diagnosed neurodegenerative disorders worldwide and poses a major challenge for both affected individuals and their caregivers. AD is a progressive neurological disorder associated with high rates of brain atrophy. Despite its durable influence on human health, understanding AD has been complicated by its enigmatic and multifactorial nature. Neurofibrillary tangles and the deposition of amyloid-beta (Aβ) protein are typical pathological features and fundamental causes of cognitive impairment in AD patients. Dysbiosis of oral and gut microbiota has been reported to induce and accelerate the formation of Aβ plaques and neurofibrillary tangles. For instance, some oral microbes can spread to the brain through cranial nerves or cellular infections, which has been suggested to increase the risk of developing AD. Importantly, the interaction between intestinal microbiota and brain cells has been recognized as influencing the development of AD as well as other neurodegenerative diseases. In particular, the metabolites produced by certain intestinal microorganisms can affect the activity of microglia and further mediate neuroinflammation, which is a leading cause of neuronal necrosis and AD pathogenesis. Which pathogens and associated pathways are involved in the development and progression of AD remains to be elucidated; however, it is well-known that gut microbiota and their metabolites can affect the brain by both direct and indirect means. Understanding the specific mechanisms involved in the interaction between these pathogens and the nervous system is vital for the early intervention in AD. In this review, we aim to comprehensively discuss the possible mechanistic pathways underlying the oral-brain, the gut-brain and the oral-gut-brain associations.

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