Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2017, Volume and Issue: 57(4), P. 1105 - 1121

Published: Jan. 6, 2017

Alzheimer's disease (AD) is a devastating neurodegenerative disorder without cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding mechanism hinders development efficacious therapeutic approaches. The loss synapses in affected brain regions correlates best with cognitive impairment patients and has been considered as early that precedes neuronal loss. Oxidative stress recognized contributing factor aging progression multiple diseases including AD. Increased production reactive oxygen species (ROS) associated age- disease-dependent mitochondrial function, altered metal homeostasis, reduced antioxidant defense directly affect synaptic activity neurotransmission neurons leading to dysfunction. In addition, molecular targets by ROS include nuclear DNA, lipids, proteins, calcium dynamics cellular architecture, receptor trafficking endocytosis, energy homeostasis. Abnormal metabolism turn could accumulation amyloid-β (Aβ) hyperphosphorylated Tau protein, which independently exacerbate dysfunction production, thereby vicious cycle. While mounting evidence implicates etiology, clinical trials therapies have not produced consistent results. this review, we will discuss role oxidative AD, innovative strategies evolved based on better complexity mechanisms dual play health disease.

Language: Английский

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Roles of tau protein in health and disease

Acta Neuropathologica, Journal Year: 2017, Volume and Issue: 133(5), P. 665 - 704

Published: April 6, 2017

Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates accompanied by synaptic dysfunction and neural cell death range neurodegenerative disorders, collectively referred to tauopathies. Recent advances our understanding the multiple functions different locations inside outside neurons have revealed novel insights its importance diverse molecular pathways including signalling, plasticity, regulation genomic stability. The present review describes physiological pathophysiological properties how these relate distribution We highlight post-translational modifications tau, which are pivotal defining modulating localisation roles health disease. include discussion other pathologically relevant changes mutation aggregation, aspects impinge on propensity propagate, potentially drive neuronal loss, diseased brain. Finally, we describe cascade events that may be driven dysfunction, impaired axonal transport, alterations synapse mitochondrial function, activation unfolded response defective degradation. It important fully understand attributed since this will provide vital information involvement development pathogenesis Such knowledge enable determination critical should targeted potential therapeutic agents developed for treatment

Language: Английский

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Neurobiological and Systemic Effects of Chronic Stress

Chronic Stress, Journal Year: 2017, Volume and Issue: 1

Published: Feb. 1, 2017

The brain is the central organ of stress and adaptation to because it perceives determines what threatening, as well behavioral physiological responses stressor, which promote ("allostasis") but also contribute pathophysiology ("allostatic load/overload") when overused dysregulated. adult developing possesses a remarkable ability show structural functional plasticity in response stressful other experiences, including neuronal replacement, dendritic remodeling synapse turnover. Stress can cause an imbalance neural circuitry subserving cognition, decision making, anxiety mood that increase or decrease expression those behaviors states. This imbalance, turn, affects systemic physiology via neuroendocrine, autonomic, immune metabolic mediators. In short term, these changes may be adaptive; but, if threat passes state persists along with circuitry, such maladaptation requires intervention combination pharmacological therapies. There are important sex differences how responds stressors. Moreover, adverse early life experience, interacting alleles certain genes, produces lasting effects on body epigenetic mechanisms. While prevention key, gives hope for therapies utilize brain-body interactions. Policies government private sector health "healthspan."

Language: Английский

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Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage

Human Molecular Genetics, Journal Year: 2011, Volume and Issue: 20(13), P. 2495 - 2509

Published: March 31, 2011

The purpose of our study was to better understand the relationship between mitochondrial structural proteins, particularly dynamin-related protein 1 (Drp1) and amyloid beta (Aβ) in progression Alzheimer's disease (AD). Using qRT-PCR immunoblotting analyses, we measured mRNA levels genes frontal cortex patients with early, definite severe AD control subjects. We also characterized monomeric oligomeric forms Aβ these patients. immunoprecipitation/immunoblotting analysis, investigated interaction Drp1. immunofluorescence determined localization Drp1 intraneuronal brains primary hippocampal neurons from precursor (AβPP) transgenic mice. found increased expression fission Fis1 (fission 1) decreased fusion Mfn1 (mitofusin 1), Mfn2 2), Opa1 (optic atrophy Tomm40. matrix gene CypD up-regulated Results analyses suggest that abnormal dynamics increase as progresses. Immunofluorescence analysis antibody antibodies 6E10 A11 revealed colocalization Aβ. interacts monomers oligomers patients, interactions are progression. Primary were accumulated had lost branches degenerated, indicating may cause neuronal degeneration. These findings AD, production crucial factors fragmentation, synaptic damage. Inhibiting, be a therapeutic strategy reduce damage cognitive decline AD.

Language: Английский

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The case for rejecting the amyloid cascade hypothesis

Nature Neuroscience, Journal Year: 2015, Volume and Issue: 18(6), P. 794 - 799

Published: May 26, 2015

Language: Английский

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Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms

Trends in Neurosciences, Journal Year: 2017, Volume and Issue: 40(3), P. 151 - 166

Published: Feb. 9, 2017

Language: Английский

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Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model

Proceedings of the National Academy of Sciences, Journal Year: 2010, Volume and Issue: 107(43), P. 18670 - 18675

Published: Oct. 11, 2010

Synaptic dysfunction and the loss of synapses are early pathological features Alzheimer's disease (AD). Synapses sites high energy demand extensive calcium fluctuations; accordingly, synaptic transmission requires levels ATP constant fluctuation. Thus, mitochondria vital for maintenance function through normal mitochondrial metabolism, distribution trafficking, modulation. To date, there has been no analysis alterations in associated with amyloid pathology an β (Aβ)-rich milieu. Here, we identified differences properties vs. nonsynaptic populations transgenic mouse brain, which overexpresses human mutant form precursor protein Aβ. Compared mitochondria, showed a greater degree age-dependent accumulation Aβ alterations. The pool was detected at age as young 4 mo, well before onset extracellular accumulation. Aβ-insulted revealed deficits function, shown by increased permeability transition, decline both respiratory activity cytochrome c oxidase, oxidative stress. Furthermore, low concentration (200 nM) significantly interfered trafficking axons. These results demonstrate that especially Aβ-rich more susceptible to Aβ-induced damage, highlighting central importance relevant development degeneration AD.

Language: Английский

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Understanding the impact of sex and gender in Alzheimer's disease: A call to action

Alzheimer s & Dementia, Journal Year: 2018, Volume and Issue: 14(9), P. 1171 - 1183

Published: June 12, 2018

Abstract Introduction Precision medicine methodologies and approaches have advanced our understanding of the clinical presentation, development, progression, management Alzheimer's disease (AD) dementia. However, sex gender not yet been adequately integrated into many these approaches. Methods The Society for Women's Health Research Interdisciplinary Network on AD, comprised an expert panel scientists clinicians, reviewed ongoing published research related to differences in AD. Results current review is a result this Network's efforts aims to: (1) highlight state‐of‐the‐science AD field differences; (2) address knowledge gaps assessing (3) discuss 12 priority areas that merit further research. Discussion exclusion has impeded faster advancement detection, treatment, care across spectrum. Greater attention will improve outcomes both sexes.

Language: Английский

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Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease

Human Molecular Genetics, Journal Year: 2011, Volume and Issue: 20(23), P. 4515 - 4529

Published: Aug. 25, 2011

Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic mitochondria causes mitochondrial failure degeneration Alzheimer's disease (AD). The purpose this study was to better understand effects Aβ activity alterations neurons from a mouse model AD. Using primary well-characterized precursor protein transgenic (AβPP) (Tg2576 line), for first time, we studied activity, including axonal transport mitochondria, dynamics, morphology function. Further, also nature Aβ-induced alterations, cell death Tg2576 mice, sought determine whether mitochondria-targeted antioxidant SS31 could mitigate oligomeric Aβ. We found significantly decreased anterograde movement, increased fission fusion, abnormal proteins defective function AβPP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed large number small structurally damaged broken cristae an apoptotic neuronal relative WT Our results intraneuronal Aβ, leading deficiencies, ultimately causing neurodegeneration cultures. However, restored viability, percentage indicating protects toxicity.

Language: Английский

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Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies

Progress in Neurobiology, Journal Year: 2013, Volume and Issue: 108, P. 21 - 43

Published: July 11, 2013

Alzheimer's disease (AD) is an age-related devastating neurodegenerative disorder, which severely impacts on the global economic development and healthcare system. Though AD has been studied for more than 100 years since 1906, exact cause(s) pathogenic mechanism(s) remain to be clarified. Also, efficient disease-modifying treatment ideal diagnostic method are unavailable. Perturbed cerebral glucose metabolism, invariant pathophysiological feature of AD, may a critical contributor pathogenesis this disease. In review, we firstly discussed features metabolism in physiological pathological conditions. Then, further reviewed contribution transportation abnormality intracellular catabolism dysfunction pathophysiology, proposed hypothesis that multiple cascades induced by impaired could result neuronal degeneration consequently cognitive deficits patients. Among these processes, altered functional status thiamine brain insulin resistance highly emphasized characterized as major mechanisms. Finally, considering fact patients exhibit hypometabolism possibly due impairments signaling also discuss some potential possibilities uncover biomarkers from abnormal develop drugs targeting at repairing impairment correcting abnormality. We conclude plays role alterations through induction factors such oxidative stress, mitochondrial dysfunction, so forth. To clarify causes, pathogeneses consequences will help break bottleneck current study finding biomarker therapy.

Language: Английский

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