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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Role of Glutamate and NMDA Receptors in Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2016, Volume and Issue: 57(4), P. 1041 - 1048

Published: Sept. 23, 2016

Excitatory glutamatergic neurotransmission via N-methyl-d-aspartate receptor (NMDAR) is critical for synaptic plasticity and survival of neurons. However, excessive NMDAR activity causes excitotoxicity promotes cell death, underlying a potential mechanism neurodegeneration occurred in Alzhei mer's disease (AD). Studies indicate that the distinct outcomes NMDAR-mediated responses are induced by regionalized activities, followed different downstream signaling pathways. The activation NMDARs initiates stimulates survival. In contrast, extrasynaptic death thus contributes to etiology AD, which can be blocked an AD drug, memantine, antagonist selectively blocks function NMDARs.

Language: Английский

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Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade

Chemical Reviews, Journal Year: 2018, Volume and Issue: 119(2), P. 1221 - 1322

Published: Aug. 10, 2018

Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow negative outlook. Although large amount research has been dedicated to elucidating pathologies neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, neurotransmitter deficiencies are pathological features shared across multiple disorders. In addition, these factors proposed be interrelated upon disease progression. Thus, development multifunctional compounds capable simultaneously interacting with several components suggested as solution undertake complex diseases. this review, we outline discuss possible therapeutic targets in Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis molecules, previously designed or discovered potential drug candidates for disorders emphasis multifunctionality. underrepresented areas discussed indicate new directions.

Language: Английский

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Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(4), P. 1469 - 1658

Published: Oct. 1, 2021

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels critical to brain function and centrally implicated numerous psychiatric neurologic disorders. There different classes iGluRs with a variety receptor subtypes each class that play distinct roles neuronal functions. The diversity iGluR subtypes, their unique functional properties roles, has motivated large number studies. Our understanding advanced considerably since first subunit gene was cloned 1989, research focus expanded encompass facets biology have been recently discovered exploit experimental paradigms made possible technological advances. Here, we review insights from more than 3 decades studies an emphasis on progress occurred past decade. We cover structure, function, pharmacology, neurophysiology, therapeutic implications for all assembled subunits encoded 18 genes. SIGNIFICANCE STATEMENT: Glutamate important virtually aspects either involved mediating some clinical features neurological disease or represent target treatment. Therefore, pharmacology this will advance our many at molecular, cellular, system levels provide new opportunities treat patients.

Language: Английский

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Tau aggregation and its interplay with amyloid-β

Acta Neuropathologica, Journal Year: 2014, Volume and Issue: 129(2), P. 207 - 220

Published: Dec. 9, 2014

Neurofibrillary tangles and amyloid plaques constitute the hallmark brain lesions of Alzheimer’s disease (AD) patients. Tangles are composed fibrillar aggregates microtubule-associated protein tau, comprise forms a proteolytic cleavage product, amyloid-β (Aβ). Although end-stage in AD, small oligomers Aβ tau now receiving increased attention as they shown to correlate best with neurotoxicity. One key question debate, however, is which these pathologies appears first hence upstream pathocascade. Studies suggest that there an intense crosstalk between two molecules and, based on work animal models, increasing evidence Aβ, at least part, exerts its toxicity via Src kinase Fyn playing crucial role this process. In other experimental paradigms, have been found exert both separate synergistic modes toxicity. The challenge, integrate different scenarios into coherent picture. Furthermore, ability therapeutic interventions targeting just one molecules, successfully neutralize other, needs be ascertained improve current strategies, such immunotherapy, for treatment AD. article not intended provide comprehensive review currently pursued we will discuss what has achieved by immunotherapy particular, how inherent limitations approach can possibly overcome novel strategies involve single-chain antibodies.

Language: Английский

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Role of Plant Derived Alkaloids and Their Mechanism in Neurodegenerative Disorders

International Journal of Biological Sciences, Journal Year: 2018, Volume and Issue: 14(3), P. 341 - 357

Published: Jan. 1, 2018

Neurodegenerative diseases are conventionally demarcated as disorders with selective loss of neurons.Conventional well newer molecules have been tested but they offer just symptomatic advantages along abundant side effects.The discovery more compelling that can halt the pathology these will be considered a miracle present time.Several synthetic compounds available may cause several other health issues.Therefore, natural from plants and sources being discovered to replace medicines.In conventional medicational therapies, reported bestow remedial effects.Phytochemicals medicinal provide better safer alternative molecules.Many phytochemicals identified cure human body number diseases.The article reviews potential efficacy plant-derived alkaloids, which possess therapeutic effects against NDDs including Alzheimer's disease (AD), Huntington (HD), Parkinson's (PD), Epilepsy, Schizophrenia, stroke.Alkaloids include isoquinoline, indole, pyrroloindole, oxindole, piperidine, pyridine, aporphine, vinca, β-carboline, methylxanthene, lycopodium, erythrine byproducts.Alkaloids constitute positive roles in ameliorating pathophysiology illnesses by functioning muscarinic adenosine receptors agonists, anti-oxidant, anti-amyloid MAO inhibitors, acetylcholinestrase butyrylcholinesterase inhibitor, inhibitor α-synuclein aggregation, dopaminergic nicotine agonist, NMDA antagonist.

Language: Английский

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The role of type 2 diabetes in neurodegeneration

Neurobiology of Disease, Journal Year: 2015, Volume and Issue: 84, P. 22 - 38

Published: April 26, 2015

Language: Английский

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Dysfunction of NMDA receptors in Alzheimer’s disease

Neurological Sciences, Journal Year: 2016, Volume and Issue: 37(7), P. 1039 - 1047

Published: March 12, 2016

N-methyl-d-aspartate receptors (NMDARs) play a pivotal role in the synaptic transmission and plasticity thought to underlie learning memory. NMDARs activation has been recently implicated Alzheimer’s disease (AD) related dysfunction. Synaptic are neuroprotective, whereas overactivation of located outside synapse cause loss mitochondrial membrane potential cell death. dysfunction glutamatergic tripartite synapse, comprising presynaptic postsynaptic neurons glial cells, is directly involved AD. This review discusses that both beta-amyloid (Aβ) tau perturb functioning including alterations glutamate release, astrocytic uptake, receptor signaling. Particular emphasis given as possible convergence point for Aβ toxicity reversible stages AD through preventive and/or disease-modifying therapeutic strategies.

Language: Английский

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Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

Frontiers in Cellular Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: April 24, 2020

Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where exacerbated or prolonged activation glutamate receptors starts cascade neurotoxicity ultimately leads to loss neuronal function and cell death. In this process, shift between normal physiological excitotoxicity largely controlled by astrocytes since they are able control levels on synaptic cleft. This achieved through clearance from cleft its underlying recycling glutamate-glutamine cycle. The molecular mechanism triggers involves alterations in calcium metabolism, dysfunction transporters, malfunction receptors, particularly NMDAR. On other hand, can be regarded as consequence cellular phenomena, such mitochondrial dysfunction, physical damage, oxidative stress. Regardless, it known excessive NMDAR results sustained influx into neurons number deleterious consequences, including reactive oxygen species overproduction, impairment buffering, release pro-apoptotic factors, among others, inevitably contribute loss. A large body evidence implicates NMDAR-mediated central pathogenesis many neurodegenerative diseases, amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy. review, we explore different causes consequences excitotoxicity, discuss involvement downstream effects several disorders, identify possible strategies study new aspects these diseases may lead discovery therapeutic approaches. With understanding common denominator perspective therapy considered, targets not specific symptoms, but phenomena disease.

Language: Английский

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Oxidative stress in alzheimer’s disease: A review on emergent natural polyphenolic therapeutics

Complementary Therapies in Medicine, Journal Year: 2019, Volume and Issue: 49, P. 102294 - 102294

Published: Dec. 31, 2019

Language: Английский

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