Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain

Background: Neurodegenerative Diseases (NDs) are age-dependent and include Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and so on. There have been numerous studies showing that accelerated aging is closely related (even the driver of) ND, thus promoting imbalances in cellular homeostasis. However, the mechanisms of how different ND types are related/triggered by advanced aging are still unclear. Therefore, there is an urgent need to explore the potential markers/mechanisms of different ND types based on aging acceleration at a system level.Methods: AD, PD, PSP, FTD, and aging markers were identified by supervised machine learning methods. The aging acceleration differential networks were constructed based on the aging score. Both the enrichment analysis and sensitivity analysis were carried out to investigate both common and specific mechanisms among different ND types in the context of aging acceleration.Results: The extracellular fluid, cellular metabolisms, and inflammatory response were identified as the common driving factors of cellular homeostasis imbalances during the accelerated aging process. In addition, Ca ion imbalance, abnormal protein depositions, DNA damage, and cytoplasmic DNA in macrophages were also revealed to be special mechanisms that further promote AD, PD, PSP, and FTD, respectively.Conclusion: The accelerated epigenetic aging mechanisms of different ND types were integrated and compared through our computational pipeline.

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The Endocannabinoid System in the Aging Brain and Neurodegenerative Diseases

Integrative Neurology ◽

10.1093/med/9780190051617.003.0014 ◽

2020 ◽

pp. 402-425

Author(s):

Daniel A. Paredes ◽

Briony J. Catlow ◽

Juan Sanchez-Ramos

Keyword(s):

Neurodegenerative Diseases ◽

Cognitive Decline ◽

Therapeutic Potential ◽

Accelerated Aging ◽

Endocannabinoid System ◽

Aging Brain ◽

Age Related ◽

Degradative Enzymes ◽

Neurochemical Changes ◽

Endogenous Cannabinoid

Aging is the major risk factor for development of cognitive decline and neurodegenerative disease. The aging brain undergoes gradual neuroanatomical and neurochemical changes, including alterations in components of the endocannabinoid system. These changes impact brain functions controlling motoric, emotive, and cognitive activities. Some degree of age-related cognitive decline occurs independent of the presence of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, neurodegenerative diseases can also develop in younger individuals who exhibit what appears to be accelerated “aging” of selective populations of neurons. The discovery of the endogenous cannabinoid system is relatively recent and began with identification of receptors in brain that interacted and bound with the main psychoactive component of the phytocannabinoid delta-9-tetrahydrocannabinol (THC). At present, the various components of the endocannabinoid system (endogenous ligands, receptors, biosynthetic and degradative enzymes) have been characterized, and research in this field is rapidly growing. In this brief review, the changes in the endocannabinoid system that occur with aging and in several classical neurodegenerative diseases are discussed with a focus on the therapeutic potential of agents that interact with various components of the endocannabinoid system.

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Chromosome Instability, Aging and Brain Diseases

Cells ◽

10.3390/cells10051256 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1256

Author(s):

Ivan Y. Iourov ◽

Yuri B. Yurov ◽

Svetlana G. Vorsanova ◽

Sergei I. Kutsev

Keyword(s):

Brain Aging ◽

Chromosome Instability ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Accelerated Aging ◽

Brain Diseases ◽

Aging Brain ◽

Ontogenetic Changes ◽

Health And Disease

Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.

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Accelerated aging in the brain, epigenetic aging in blood, and polygenic risk for schizophrenia

Schizophrenia Research ◽

10.1016/j.schres.2021.04.005 ◽

2021 ◽

Vol 231 ◽

pp. 189-197

Author(s):

Jalmar Teeuw ◽

Anil P.S. Ori ◽

Rachel M. Brouwer ◽

Sonja M.C. de Zwarte ◽

Hugo G. Schnack ◽

...

Keyword(s):

Accelerated Aging ◽

Polygenic Risk ◽

Epigenetic Aging ◽

The Brain

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Molecular and cellular pathways contributing to brain aging

Behavioral and Brain Functions ◽

10.1186/s12993-021-00179-9 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Aliabbas Zia ◽

Ali Mohammad Pourbagher-Shahri ◽

Tahereh Farkhondeh ◽

Saeed Samarghandian

Keyword(s):

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Brain Aging ◽

Neuroprotective Effect ◽

Ros Generation ◽

Brain Health ◽

Cellular Pathways ◽

Aging Mechanisms ◽

Oxidatively Modified ◽

Biology Of Aging

AbstractAging is the leading risk factor for several age-associated diseases such as neurodegenerative diseases. Understanding the biology of aging mechanisms is essential to the pursuit of brain health. In this regard, brain aging is defined by a gradual decrease in neurophysiological functions, impaired adaptive neuroplasticity, dysregulation of neuronal Ca2+ homeostasis, neuroinflammation, and oxidatively modified molecules and organelles. Numerous pathways lead to brain aging, including increased oxidative stress, inflammation, disturbances in energy metabolism such as deregulated autophagy, mitochondrial dysfunction, and IGF-1, mTOR, ROS, AMPK, SIRTs, and p53 as central modulators of the metabolic control, connecting aging to the pathways, which lead to neurodegenerative disorders. Also, calorie restriction (CR), physical exercise, and mental activities can extend lifespan and increase nervous system resistance to age-associated neurodegenerative diseases. The neuroprotective effect of CR involves increased protection against ROS generation, maintenance of cellular Ca2+ homeostasis, and inhibition of apoptosis. The recent evidence about the modem molecular and cellular methods in neurobiology to brain aging is exhibiting a significant potential in brain cells for adaptation to aging and resistance to neurodegenerative disorders.

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Anti–Na+/K+-ATPase immunotherapy ameliorates α-synuclein pathology through activation of Na+/K+-ATPase α1–dependent autophagy

Science Advances ◽

10.1126/sciadv.abc5062 ◽

2021 ◽

Vol 7 (5) ◽

pp. eabc5062

Author(s):

Lei Cao ◽

Siping Xiong ◽

Zhiyuan Wu ◽

Lei Ding ◽

Yebo Zhou ◽

...

Keyword(s):

Monoclonal Antibody ◽

Tyrosine Hydroxylase ◽

Neurodegenerative Diseases ◽

Motor Function ◽

Therapeutic Strategy ◽

Underlying Mechanism ◽

Behavioral Tests ◽

Behavioral Deficits ◽

Cellular Homeostasis ◽

Beneficial Effects

Na+/K+-ATPase (NKA) plays important roles in maintaining cellular homeostasis. Conversely, reduced NKA activity has been reported in aging and neurodegenerative diseases. However, little is known about the function of NKA in the pathogenesis of Parkinson’s disease (PD). Here, we report that reduction of NKA activity in NKAα1+/− mice aggravates α-synuclein–induced pathology, including a reduction in tyrosine hydroxylase (TH) and deficits in behavioral tests for memory, learning, and motor function. To reverse this effect, we generated an NKA-stabilizing monoclonal antibody, DR5-12D, against the DR region (897DVEDSYGQQWTYEQR911) of the NKAα1 subunit. We demonstrate that DR5-12D can ameliorate α-synuclein–induced TH loss and behavioral deficits by accelerating α-synuclein degradation in neurons. The underlying mechanism for the beneficial effects of DR5-12D involves activation of NKAα1-dependent autophagy via increased AMPK/mTOR/ULK1 pathway signaling. Cumulatively, this work demonstrates that NKA activity is neuroprotective and that pharmacological activation of this pathway represents a new therapeutic strategy for PD.

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New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210198 ◽

2021 ◽

pp. 1-29

Author(s):

David R. Elmaleh ◽

Matthew A. Downey ◽

Ljiljana Kundakovic ◽

Jeremy E. Wilkinson ◽

Ziv Neeman ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Gut Microbiome ◽

Treatment Options ◽

Treatment Strategies ◽

Modern Society ◽

Aging Brain ◽

New Approaches ◽

Microbiome Profile ◽

Carry Over

Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer’s disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual’s manifestation of AD as influenced by a coercive inflammatory gut.

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Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases

Veterinary Pathology ◽

10.1177/0300985815623997 ◽

2016 ◽

Vol 53 (2) ◽

pp. 327-348 ◽

Cited By ~ 47

Author(s):

S. A. Youssef ◽

M. T. Capucchio ◽

J. E. Rofina ◽

J. K. Chambers ◽

K. Uchida ◽

...

Keyword(s):

Animal Models ◽

Neurodegenerative Diseases ◽

Laboratory Animals ◽

Aging Brain

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A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

Microbiome ◽

10.1186/s40168-021-01172-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Hongli Shi ◽

Xing Ge ◽

Xi Ma ◽

Mingxuan Zheng ◽

Xiaoying Cui ◽

...

Keyword(s):

Cognitive Impairment ◽

Gut Microbiota ◽

Neurodegenerative Diseases ◽

Dietary Fiber ◽

Brain Aging ◽

Synaptic Proteins ◽

Aging Brain ◽

Normal Brain ◽

Fiber Intake ◽

Synaptic Ultrastructure

Abstract Background Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis. Results In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment. Conclusions This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases.

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