Neural Dedifferentiation in the Aging Brain

Trends in Cognitive Sciences, Journal Year: 2019, Volume and Issue: 23(7), P. 547 - 559

Published: June 4, 2019

Language: Английский

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GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2020, Volume and Issue: 16(9), P. 1312 - 1329

Published: June 16, 2020

To propose a new hypothesis that GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease (AD).Synaptic E/I emerge decades before appearance cognitive decline AD patients, which contribute to neurodegeneration. Initially, was thought occur first, due glutamatergic cholinergic systems. However, evidence has demonstrated system, counterpart balance major neurotransmitter system central nervous is altered enormously this contributes further pathogenesis.Alterations induced by multiple pathogenic or risk factors, pathogenesis.This accounts for many critical questions common challenges confronting pathogenesis. More specifically, it explains why amyloid beta (Aβ), β-secretase (BACE1), apolipoprotein E4 gene (APOE ε4), hyperactive glia cells, age sex are factors AD. promotes spread Aβ pathology throughout brain associated impairments, induction these varied shares neurobiology leading imbalance. In turn, some exacerbate Moreover, modulates various functions thus, nonamnestic manifestations. Furthermore, corrections through manipulation have shown positive outcomes preclinical clinical studies, suggesting potential as therapeutic target AD.Dysfunction signaling pathways, include existing theories pathogenesis, such neuroinflammation hypotheses. perspective, related excitotoxicity, Therefore, could be key restore, at least partially, function patients.

Language: Английский

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GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease

Seminars in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 116, P. 146 - 159

Published: Feb. 9, 2021

In this review, we focus on the potential role of γ-aminobutyric acidergic (GABAergic) system in age-related episodic memory impairments humans, with a particular Alzheimer's disease (AD). Well-established animal models have shown that GABA plays central regulating and synchronizing neuronal signaling hippocampus, brain area critical for undergoes early significant morphologic functional changes course AD. Neuroimaging research humans has documented hyperactivity hippocampus losses resting state connectivity Default Mode Network, network itself prominently includes hippocampus-presaging decline individuals at-risk Apolipoprotein ε4, highest genetic risk factor AD, is associated GABAergic dysfunction models, humans. combination, these findings suggest may be linchpin complex factors eventually leads to principal clinical hallmark AD: loss. Here, will review current literature supporting hypothesis. First, molecular cellular basis its cognition. Next, report evidence dysregulations AD normal aging, both human studies. Finally, outline model based results neuroimaging studies which hippocampal tasks concurrent even preceding diagnosis, along modulate association.

Language: Английский

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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 20, 2023

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of (NDAs), such as Alzheimer’s disease, Parkinson’s Huntington’s Amyotrophic lateral sclerosis. Glucose is the major brain fuel glucose hypometabolism has been observed regions vulnerable to NDAs. Many susceptible are topological central hub connectome, linked by densely interconnected long-range axons. Axons, key components have high metabolic needs support neurotransmission other essential activities. Long-range axons particularly injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy often an early sign neurodegeneration. Recent ascribe axonal maintenance failures local dysregulation. With this review, we aim stimulate research exploring metabolically oriented neuroprotection strategies enhance or normalize bioenergetics NDA models. Here start summarizing evidence from human patients animal models reveal correlation between connectomic disintegration aging/NDAs. To encourage mechanistic investigations on how dysregulation occurs during aging/NDAs, first review current literature distinct subdomains: axon initial segments, myelinated arbors harboring pre-synaptic boutons. In each subdomain, focus organization, activity-dependent regulation system, external glial support. Second, mechanisms regulating nicotinamide adenine dinucleotide (NAD + ) homeostasis, molecule for energy metabolism processes, including NAD biosynthetic, recycling, consuming pathways. Third, highlight innate vulnerability connectome discuss its perturbation As deficits developing into NDAs, especially asymptomatic phase, they likely exaggerated further impaired energetic cost neural network hyperactivity, pathology. Future interrogating causal relationship vulnerability, axonopathy, amyloid/tau pathology, cognitive decline will provide fundamental knowledge therapeutic interventions.

Language: Английский

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The regulation of glutamic acid decarboxylases in GABA neurotransmission in the brain

Archives of Pharmacal Research, Journal Year: 2019, Volume and Issue: 42(12), P. 1031 - 1039

Published: Nov. 30, 2019

Language: Английский

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Arousal increases neural gain via the locus coeruleus–noradrenaline system in younger adults but not in older adults

Nature Human Behaviour, Journal Year: 2018, Volume and Issue: 2(5), P. 356 - 366

Published: April 27, 2018

Language: Английский

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Separating vascular and neuronal effects of age on fMRI BOLD signals

Philosophical Transactions of the Royal Society B Biological Sciences, Journal Year: 2020, Volume and Issue: 376(1815), P. 20190631 - 20190631

Published: Nov. 16, 2020

Accurate identification of brain function is necessary to understand the neurobiology cognitive ageing, and thereby promote well-being across lifespan. A common tool used investigate neurocognitive ageing functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms neuronal activity, blood oxygenation level-dependent (BOLD) signal measured by includes contributions both vascular factors, which change differentially with age. While some studies results these not well known within field therefore confounds common. Despite over 10 000 BOLD-fMRI papers on fewer than 20 have applied techniques correct for effects. neurovascular only a confound fMRI, but an important feature its own right, be assessed alongside measures ageing. We review current approaches dissociate components regional activity connectivity. highlight emerging evidence that mechanisms do simply control flow support metabolic needs neurons, form complex interactions influence health disease. This article part theme issue ‘Key relationships between non-invasive neuroimaging underlying activity’.

Language: Английский

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Roles of taurine in cognitive function of physiology, pathologies and toxication

Life Sciences, Journal Year: 2019, Volume and Issue: 231, P. 116584 - 116584

Published: June 18, 2019

Language: Английский

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Cognitive impairment and depression: Meta-analysis of structural magnetic resonance imaging studies

NeuroImage Clinical, Journal Year: 2021, Volume and Issue: 32, P. 102830 - 102830

Published: Jan. 1, 2021

Longitudinal comorbidity of depression and cognitive impairment has been reported by number epidemiological studies but the underlying mechanisms explaining link between affective problems decline are not very well understood. Imaging have typically investigated patients with major depressive disorder (MDD) mild (MCI) separately thus identified a structural brain signature common to these conditions that may illuminate potentially targetable shared biological mechanisms. We performed meta-analysis of. 48 voxel-based morphometry (VBM) individuals MDD, MCI, age-matched controls demonstrated MDD MCI had volumetric reductions in regions including insula, superior temporal gyrus (STG), inferior frontal gyrus, amygdala, hippocampus, thalamus. suggest insula STG might reflect communication deficits infrequent participation mentally or socially stimulating activities, which described as risk factors for both MDD. also disease-specific changes symptoms such poor integration emotional information, feelings helplessness worthlessness, anhedonia These findings could contribute better understanding origins MDD-MCI facilitate development early interventions.

Language: Английский

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Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors

Frontiers in Molecular Neuroscience, Journal Year: 2019, Volume and Issue: 12

Published: July 24, 2019

α5 subunit containing GABA type A receptors (GABAARs) have long been an enigmatic receptor subtype of interest due to their specific brain distribution, unusual surface localization and key role in synaptic plasticity, cognition memory. These are uniquely positioned sculpt both the developing mature hippocampal circuitry high overall expression a distinct peak within critical synapse formation period during second postnatal week. Unlike majority other GABAARs, they exhibit clustering at extrasynaptic sites via interactions with radixin scaffold as well gephyrin, thus contributing respectively tonic currents GABAergic neurotransmission. GABAAR signaling can be altered neurodevelopmental disorders including autism mental retardation by inflammation CNS injury disease. Due unique physiology pharmacology drugs targeting these being developed tested treatments for disorders, depression, schizophrenia, mild cognitive impairment. This review article focuses on advances understanding how contributes neurobiology. In particular, I discuss recent insights remaining knowledge gaps functional receptors, pathologies associated dysfunction, effects potential therapeutic uses targeted drugs.

Language: Английский

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