bims-metalz 2023-03-12 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2023–03–12
nine papers selected by
Mikaila Chetty, Goa University

Gut microbiota, an additional hallmark of human aging and neurodegeneration.
Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy.
Role of microbial dysbiosis in the pathogenesis of Alzheimer's disease.
Bifidobacterium breve HNXY26M4 Attenuates Cognitive Deficits and Neuroinflammation by Regulating the Gut-Brain Axis in APP/PS1 Mice.
Crosstalk between Oxidative Stress and Aging in Neurodegeneration Disorders.
Mitochondria Localized microRNAs: An Unexplored miRNA Niche in Alzheimer's Disease and Aging.
Mitochondrial mechanisms in Alzheimer's disease: quest for therapeutics.
Unlocking Modifiable Risk Factors for Alzheimer's Disease: Does the Oral Microbiome Hold Some of the Keys?
Tau, RNA, and RNA-Binding Proteins: Complex Interactions in Health and Neurodegenerative Diseases.

Neuroscience. 2023 Mar 07. pii: S0306-4522(23)00092-1. [Epub ahead of print]

Gut microbiota, an additional hallmark of human aging and neurodegeneration.

Natalia Molinero, Alejandro Antón, Félix Hernández, Jesús Ávila, Begoña Bartolomé, M Victoria Moreno-Arribas.

  Gut microbiota represents a diverse and dynamic population of microorganisms harbouring the gastrointestinal tract, which influences host health and disease. Bacterial colonization of the gastrointestinal tract begins at birth and changes throughout life, with age being one of the conditioning factors for its vitality. Aging is also a primary risk factor for most neurodegenerative diseases. Among them, Alzheimeŕs disease (AD) is probably the one where its association with a state of dysbiosis of the gut microbiota has been most studied. In particular, intestinal microbial-derived metabolites have been associated with β-amyloid formation and brain amyloid deposition, tau phosphorylation, as well as neuroinflammation in AD patients. Moreover, it has been suggested that some oral bacteria increase the risk of developing AD. However, the causal connections among microbiome, amyloid-tau interaction, and neurodegeneration need to be addressed. This paper summarizes the emerging evidence in the literature regarding the link between the oral and gut microbiome and neurodegeneration with a focus on AD. Taxonomic features of bacteria as well as microbial functional alterations associated with AD biomarkers are the main points reviewed. Data from clinical studies as well as the link between microbiome and clinical determinants of AD are particularly emphasized. Further, relationships between gut microbiota and age-dependent epigenetic changes and other neurological disorders are also described. Together, all this evidence suggests that, in some sense, gut microbiota can be seen as an additional hallmark of human aging and neurodegeneration.

Keywords:  Alzheimer’s disease; aging; epigenetic alterations; gut microbiome; neurodegeneration; oral-gut-brain axis

DOI:  https://doi.org/10.1016/j.neuroscience.2023.02.014
Nature. 2023 Mar 08.

Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy.

Xiaoying Chen, Maria Firulyova, Melissa Manis, Jasmin Herz, Igor Smirnov, Ekaterina Aladyeva, Chanung Wang, Xin Bao, Mary Beth Finn, Hao Hu, Irina Shchukina, Min Woo Kim, Carla M Yuede, Jonathan Kipnis, Maxim N Artyomov, Jason D Ulrich, David M Holtzman.

Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer's disease1,2. The regional progression of brain atrophy in Alzheimer's disease highly correlates with tau accumulation but not amyloid deposition3-5, and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer's disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer's disease and primary tauopathies.

DOI: https://doi.org/10.1038/s41586-023-05788-0
Neuropharmacology. 2023 Mar 05. pii: S0028-3908(23)00068-0. [Epub ahead of print]229 109478

Role of microbial dysbiosis in the pathogenesis of Alzheimer's disease.

Gudimetla Susmitha, Rahul Kumar.

  Alzheimer's disease (AD) is the leading cause of dementia in the elderly and detected during the advanced stages where the chances of reversal are minimum. The gut-brain axis mediates a bidirectional communication between the gut and brain, which is dependent on bacterial products such as short chain fatty acids (SCFA) and neurotransmitters. Accumulating lines of evidence suggests that AD is associated with significant alteration in the composition of gut microbiota. Furthermore, transfer of gut microbiota from healthy individuals to patients can reshape the gut microbiota structure and thus holds the potential to be exploited for the treatment of various neurodegenerative disease. Moreover, AD-associated gut dysbiosis can be partially reversed by using probiotics, prebiotics, natural compounds and dietary modifications, but need further validations. Reversal of AD associated gut dysbiosis alleviate AD-associated pathological feature and therefore can be explored as a therapeutic approach in the future. The current review article will describe various studies suggesting that AD dysbiosis occurs with AD and highlights the causal role by focussing on the interventions that hold the potential to reverse the gut dysbiosis partially.

Keywords:  Amyloid; Gut-brain axis; Microbiota; Neurodegeneration; Tau

DOI:  https://doi.org/10.1016/j.neuropharm.2023.109478
J Agric Food Chem. 2023 Mar 08.

Bifidobacterium breve HNXY26M4 Attenuates Cognitive Deficits and Neuroinflammation by Regulating the Gut-Brain Axis in APP/PS1 Mice.

Guangsu Zhu, Jianxin Zhao, Gang Wang, Wei Chen.

  Alzheimer's disease (AD) is a neurodegenerative disease, pathological markers of which are amyloid plaques and neurofibrillary tangles. As a key node of gut-brain axis, gut microbiota is increasingly associated with changes in cognitive behaviors and brain function. Psychobiotics are known to benefit patients with neurodegenerative diseases by the production and deliberation of neuroactive substances. However, psychobiotics are strain-specific probiotics, and their neuroprotective effects on the brain and modulation effects on the gut microbiome are not generalizable. In this study, we investigated the effects of Bifidobacterium breve HNXY26M4 in APP/PS1 mice. By assessing the alterations associated with brain function, we found that B. breve HNXY26M4 attenuated cognitive deficits and suppressed neuroinflammation and synaptic dysfunction in APP/PS1 mice. Moreover, by determining the modulation effects of B. breve HNXY26M4 on gut homeostasis, we identified that B. breve HNXY26M4 supplementation restored the composition of gut microbiota and short-chain fatty acids, as well as enhanced the function of the intestinal barrier. These findings indicate that microbiome-derived acetate and butyrate modulated by B. breve HNXY26M4 administration may be transported to the brain through the blood-brain barrier, and thus confer neuroprotective effects against AD-associated brain deficits and inflammation via the gut-brain axis.

Keywords:  Alzheimer’s disease; Bifidobacterium breve; cognition; gut−brain axis; short-chain fatty acids

DOI:  https://doi.org/10.1021/acs.jafc.3c00652
Cells. 2023 Feb 27. pii: 753. [Epub ahead of print]12(5):

Crosstalk between Oxidative Stress and Aging in Neurodegeneration Disorders.

Rehab F Abdelhamid, Seiichi Nagano.

  The world population is aging rapidly, and increasing lifespan exacerbates the burden of age-related health issues. On the other hand, premature aging has begun to be a problem, with increasing numbers of younger people suffering aging-related symptoms. Advanced aging is caused by a combination of factors: lifestyle, diet, external and internal factors, as well as oxidative stress (OS). Although OS is the most researched aging factor, it is also the least understood. OS is important not only in relation to aging but also due to its strong impact on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). In this review, we will discuss the aging process in relation to OS, the function of OS in neurodegenerative disorders, and prospective therapeutics capable of relieving neurodegenerative symptoms associated with the pro-oxidative condition.

Keywords:  aging; free radical; neurodegenerative diseases; oxidative stress

DOI:  https://doi.org/10.3390/cells12050753
Cells. 2023 Feb 25. pii: 742. [Epub ahead of print]12(5):

Mitochondria Localized microRNAs: An Unexplored miRNA Niche in Alzheimer's Disease and Aging.

Jazmin Rivera, Laxman Gangwani, Subodh Kumar.

  Mitochondria play several vital roles in the brain cells, especially in neurons to provide synaptic energy (ATP), Ca2+ homeostasis, Reactive Oxygen Species (ROS) production, apoptosis, mitophagy, axonal transport and neurotransmission. Mitochondrial dysfunction is a well-established phenomenon in the pathophysiology of many neurological diseases, including Alzheimer's disease (AD). Amyloid-beta (Aβ) and Phosphorylated tau (p-tau) proteins cause the severe mitochondrial defects in AD. A newly discovered cellular niche of microRNAs (miRNAs), so-called mitochondrial-miRNAs (mito-miRs), has recently been explored in mitochondrial functions, cellular processes and in a few human diseases. The mitochondria localized miRNAs regulate local mitochondrial genes expression and are significantly involved in the modulation of mitochondrial proteins, and thereby in controlling mitochondrial function. Thus, mitochondrial miRNAs are crucial to maintaining mitochondrial integrity and for normal mitochondrial homeostasis. Mitochondrial dysfunction is well established in AD pathogenesis, but unfortunately mitochondria miRNAs and their precise roles have not yet been investigated in AD. Therefore, an urgent need exists to examine and decipher the critical roles of mitochondrial miRNAs in AD and in the aging process. The current perspective sheds light on the latest insights and future research directions on investigating the contribution of mitochondrial miRNAs in AD and aging.

Keywords:  Alzheimer’s disease; aging; mitochondrial dysfunction; mitochondrial miRNAs; synaptic energy

DOI:  https://doi.org/10.3390/cells12050742
Drug Discov Today. 2023 Mar 03. pii: S1359-6446(23)00063-6. [Epub ahead of print] 103547

Mitochondrial mechanisms in Alzheimer's disease: quest for therapeutics.

Komal Kalani, Poonam Chaturvedi, Pankaj Chaturvedi, Vinod Kumar Verma, Nand Lal, Sudhir K Awasthi, Anuradha Kalani.

  Mitochondrial function is essential for maintaining neuronal integrity, because neurons have a high energy demand. Neurodegenerative diseases, such as Alzheimer's disease (AD), are exacerbated by mitochondrial dysfunction. Mitochondrial autophagy (mitophagy) attenuates neurodegenerative diseases by eradicating dysfunctional mitochondria. In neurodegenerative disorders, there is disruption of the mitophagy process. High levels of iron also interfere with the mitophagy process and the mtDNA released after mitophagy is proinflammatory and triggers the cGAS-STING pathway that aids AD pathology. In this review, we critically discuss the factors that affect mitochondrial impairment and different mitophagy processes in AD. Furthermore, we discuss the molecules used in mouse studies as well as clinical trials that could result in potential therapeutics in the future. Teaser: This review reports the novel therapeutic molecules that are underway in clinical trials for neurodegenerative diseases like Alzheimer's disease, demonstrating how mitochondria become dysfunctional and how they can be rescued.

Keywords:  Alzheimer’s disease; bioenergetics; exosomes; mitochondria; mitophagy; neurodegenerative disorders

DOI:  https://doi.org/10.1016/j.drudis.2023.103547
J Alzheimers Dis. 2023 Feb 27.

Unlocking Modifiable Risk Factors for Alzheimer's Disease: Does the Oral Microbiome Hold Some of the Keys?

Amy Loughman, Christina Adler, Helen Macpherson.

  Advancing age is recognized as the primary risk factor for Alzheimer's disease (AD); however approximately one third of dementia cases are attributable to modifiable risk factors such as hypertension, diabetes, smoking, and obesity. Recent research also implicates oral health and the oral microbiome in AD risk and pathophysiology. The oral microbiome contributes to the cerebrovascular and neurodegenerative pathology of AD via the inflammatory, vascular, neurotoxic, and oxidative stress pathways of known modifiable risk factors. This review proposes a conceptual framework that integrates the emerging evidence regarding the oral microbiome with established modifiable risk factors. There are numerous mechanisms by which the oral microbiome may interact with AD pathophysiology. Microbiota have immunomodulatory functions, including the activation of systemic pro-inflammatory cytokines. This inflammation can affect the integrity of the blood-brain barrier, which in turn modulates translocation of bacteria and their metabolites to brain parenchyma. Amyloid-β is an antimicrobial peptide, a feature which may in part explain its accumulation. There are microbial interactions with cardiovascular health, glucose tolerance, physical activity, and sleep, suggesting that these modifiable lifestyle risk factors of dementia may have microbial contributors. There is mounting evidence to suggest the relevance of oral health practices and the microbiome to AD. The conceptual framework presented here additionally demonstrates the potential for the oral microbiome to comprise a mechanistic intermediary between some lifestyle risk factors and AD pathophysiology. Future clinical studies may identify specific oral microbial targets and the optimum oral health practices to reduce dementia risk.

Keywords:  Alzheimer’s disease; dementia; healthy lifestyle; microbiota; oral health; periodontal diseases

DOI:  https://doi.org/10.3233/JAD-220760
Neuroscientist. 2023 Mar 09. 10738584231154551

Tau, RNA, and RNA-Binding Proteins: Complex Interactions in Health and Neurodegenerative Diseases.

Evan Lester, Roy Parker.

  The tau protein is a key contributor to multiple neurodegenerative diseases. The pathology of tau is thought to be related to tau's propensity to form self-templating fibrillar structures that allow tau fibers to propagate in the brain by prion-like mechanisms. Unresolved issues with respect to tau pathology are how the normal function of tau and its misregulation contribute to disease, how cofactors and cellular organelles influence the initiation and propagation of tau fibers, and determining the mechanism of tau toxicity. Herein, we review the connection between tau and degenerative diseases, the basis for tau fibrilization, and how that process interacts with cellular molecules and organelles. One emerging theme is that tau interacts with RNA and RNA-binding proteins, normally and in pathologic aggregates, which may provide insight into alterations in RNA regulation observed in disease.

Keywords:  Alzheimer; RNA; RNA-binding proteins; frontotemporal dementia; membraneless organelles; neurodegeneration; tau

DOI:  https://doi.org/10.1177/10738584231154551