Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration

Neural Plasticity, Journal Year: 2016, Volume and Issue: 2016, P. 1 - 15

Published: Jan. 1, 2016

Stress and stress hormones, glucocorticoids (GCs), exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation synaptic structure, transmission glial function to behavior. Their are mediated by glucocorticoid mineralocorticoid receptors which nuclear receptors/transcription factors. While GCs primarily act maintain homeostasis inducing physiological behavioral adaptation, prolonged exposure elevated GC levels may result neuro- psychopathology. There is now ample evidence for cause-effect relationships between stress, levels, cognitive mood disorders while a link chronic stress/GC neurodegenerative such as Alzheimer’s (AD) Parkinson’s (PD) diseases growing. This brief review considers some mechanisms through contribute pathogenesis AD PD.

Language: Английский

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Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

Chemical Communications, Journal Year: 2015, Volume and Issue: 51(70), P. 13434 - 13450

Published: Jan. 1, 2015

Our Feature Article details the physiological role of amyloid beta (Aβ), elaborates its toxic effects and outlines therapeutic molecules designed in last two years targeting different aspects Aβ for preventing AD.

Language: Английский

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Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2016, Volume and Issue: 132(2), P. 235 - 256

Published: March 18, 2016

Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded swollen presynaptic dystrophic neurites consisting dysfunctional axons and terminals that accumulate β-site precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular molecular mechanisms govern neurite formation are unclear, elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest disrupt microtubules, which we hypothesize have a critical role in development dystrophies. To investigate this further, here assessed effects Aβ, particularly neurotoxic Aβ42, on microtubules during vitro vivo. Live-cell imaging primary neurons revealed exposure Aβ42 oligomers caused varicose beaded with extensive microtubule disruption, inhibited anterograde retrograde trafficking. In brain sections from patients 5XFAD transgenic mouse model pathology, halos BACE1 elevation around exhibited aberrant tubulin accumulations or voids. At ultrastructural level, peri-plaque dystrophies were strikingly devoid replete multi-lamellar vesicles resembling autophagic intermediates. Proteins motors, kinesin dynein, other neuronal proteins aberrantly localized Inactive pro-cathepsin D also accumulated dystrophies, indicating reduced lysosomal function. Most importantly, accumulation increased cleavage APP Our study supports hypothesis induces disruption surround plaques, thus impairing axonal transport leading exacerbation pathology AD.

Language: Английский

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Plant alkaloids as drug leads for Alzheimer's disease

Neurochemistry International, Journal Year: 2015, Volume and Issue: 89, P. 260 - 270

Published: July 26, 2015

Language: Английский

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Inhibition of Drp1 Ameliorates Synaptic Depression, Aβ Deposition, and Cognitive Impairment in an Alzheimer's Disease Model

Journal of Neuroscience, Journal Year: 2017, Volume and Issue: 37(20), P. 5099 - 5110

Published: April 21, 2017

Excessive mitochondrial fission is a prominent early event and contributes to dysfunction, synaptic failure, neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains be determined whether inhibition excessive beneficial mammal models AD. To determine dynamin-related protein 1 (Drp1), key regulator fragmentation, can disease-modifying therapeutic target for AD, we examined effects Drp1 inhibitor on dysfunctions induced by oligomeric amyloid-β (Aβ) neurons neuropathology cognitive functions Aβ precursor protein/presenilin double-transgenic AD mice. Inhibition alleviates loss membrane potential, reactive oxygen species production, ATP reduction, depression Aβ-treated neurons. Furthermore, significantly improves learning memory prevents lipid peroxidation, BACE1 expression, deposition brain model. These results provide evidence that plays an important role Aβ-mediated AD-related decline animal Therefore, inhibiting Drp1-mediated may efficient avenue SIGNIFICANCE STATEMENT Mitochondrial relies evolutionary conserved (Drp1). activity mitochondria fragmentation are elevated brains sporadic (AD) cases. In present study, first demonstrated restored (Aβ)-mediated reduced As result, deficits mice were rescued inhibition. suggest combined attributed hyperactivation pathogenesis inhibitors fission, such as inhibitors, new strategy

Language: Английский

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Molecular and Cellular Basis of Neurodegeneration in Alzheimer’s Disease

Molecules and Cells, Journal Year: 2017, Volume and Issue: 40(9), P. 613 - 620

Published: Sept. 1, 2017

The most common form of senile dementia is Alzheimer's disease (AD), which characterized by the extracellular deposition amyloid -peptide (A) plaques and intracellular formation neurofibrillary tangles (NFTs) in cerebral cortex.Tau abnormalities are commonly observed many neurodegenerative diseases including AD, Parkinson's disease, Pick's disease.Interestingly, tau-mediated NFTs AD brains shows better correlation with cognitive impairment than A plaque accumulation; pathological tau alone sufficient to elicit frontotemporal dementia, but it does not cause AD.A growing amount evidence suggests that soluble oligomers concert hyperphosphorylated (pTau) serve as major pathogenic drivers neurodegeneration AD.Increased trigger neuronal dysfunction network alternations learning memory circuitry prior clinical onset leading decline.Furthermore, accumulated damage mitochondria course aging, best-known nongenetic risk factor for may collaborate pTau induce synapse loss AD.In this review, I summarize discuss current knowledge molecular cellular biology also mechanisms underlie A-mediated neurodegeneration.

Language: Английский

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Memantine for the Treatment of Dementia: A Review on its Current and Future Applications

Journal of Alzheimer s Disease, Journal Year: 2017, Volume and Issue: 62(3), P. 1223 - 1240

Published: Dec. 15, 2017

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence in brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning memory. An excessive activation NMDARs has been associated with neuronal loss. discovery extrasynaptic provided rational physiological explanation between excitotoxic actions glutamate. Memantine (MEM), an antagonist NMDAR, currently used treatment AD jointly acetylcholinesterase inhibitors. It demonstrated that MEM preferentially prevents continuous NMDAR therefore cell death induced excitotoxicity without disrupting synaptic activity. problem shown no clear positive effects clinical applications while, preclinical stages, had very promising results. data studies suggests impact on improving neuropathology, as well preventing Aβ production, aggregation, or downstream neurotoxic consequences, part through blockade NMDAR. Thus, focus this review primarily to discuss efficacy models AD, consider possible combinations drug others, then evaluate reasons its lack trials. Finally, other pathologies also considered.

Language: Английский

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Melatonin ameliorates amyloid beta‐induced memory deficits, tau hyperphosphorylation and neurodegeneration via PI3/Akt/GSk3β pathway in the mouse hippocampus

Journal of Pineal Research, Journal Year: 2015, Volume and Issue: 59(1), P. 47 - 59

Published: April 7, 2015

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, pathologically characterized by accumulation of amyloid beta (Aβ) aggregation in brain, and considered to be primary cause cognitive dysfunction. Aβ aggregates lead synaptic disorder, tau hyperphosphorylation, neurodegeneration. In this study, underlying neuroprotective mechanism melatonin against Aβ1-42-induced neurotoxicity was investigated mice hippocampus. Intracerebroventricular (i.c.v.) Aβ1-42-injection triggered memory impairment, hyperphosphorylation protein, neurodegeneration After 24 hr Aβ1-42 injection, were treated with (10 mg/kg, intraperitonially) for 3 wks, reversed disorder via increasing level presyanptic (Synaptophysin SNAP-25) postsynaptic protein [PSD95, p-GluR1 (Ser845), SNAP23, p-CREB (Ser133)], respectively, attenuated impairment. Chronic treatment PI3K/Akt/GSK3β signaling activating p-PI3K, p-Akt (Ser 473) p-GSK3β (Ser9) Aβ1-42-treated mice. Furthermore, decreased -induced apoptosis through decreasing overexpression caspase-9, caspase-3, PARP-1 level. Additionally, evaluation immunohistochemical analysis Fluorojade-B, Nissl staining indicated that prevented Our results demonstrated has effect mouse model AD. On basis these results, we suggest could an effective, promising, safe candidate progressive disorders, such as

Language: Английский

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Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases

Mediators of Inflammation, Journal Year: 2015, Volume and Issue: 2015(1)

Published: Jan. 1, 2015

Neurodegeneration is a chronic progressive loss of neuronal cells leading to deterioration central nervous system (CNS) functionality. It has been shown that neuroinflammation precedes neurodegeneration in various neurodegenerative diseases. Matrix metalloproteinases (MMPs), protein family zinc‐containing endopeptidases, are essential (neuro)inflammation and might be involved neurodegeneration. Although MMPs indispensable for physiological development functioning the organism, they often referred as double‐edged swords due their ability also inflict substantial damage pathological conditions. MMP activity strictly controlled, its dysregulation leads variety pathologies. Investigation potential use therapeutic targets requires better understanding contributions Here, we review roles diseases: Alzheimer’s disease (AD), Parkinson’s (PD), amyotrophic lateral sclerosis (ALS), Huntington’s (HD), multiple (MS). We discuss inhibition possible strategy treat

Language: Английский

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Synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic strategies

Pharmacology & Therapeutics, Journal Year: 2018, Volume and Issue: 195, P. 186 - 198

Published: Nov. 12, 2018

Language: Английский

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