Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2020, Volume and Issue: 15(1)

Published: July 16, 2020

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There currently no effective treatment for AD, which may be attributed part to lack of a clear underlying mechanism. Studies within last few decades provide growing evidence central role amyloid β (Aβ) and tau, as well glial contributions various molecular cellular pathways AD pathogenesis. Herein, we review recent progress with respect Aβ- tau-associated mechanisms, discuss dysfunction emphasis on neuronal receptors that mediate Aβ-induced toxicity. We also other critical factors affect pathogenesis, including genetics, aging, variables related environment, lifestyle habits, describe potential apolipoprotein E (APOE), viral bacterial infection, sleep, microbiota. Although have gained much towards understanding aspects this devastating disorder, greater commitment research mechanism, diagnostics will needed future research.

Language: Английский

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Glial Cells: Role of the Immune Response in Ischemic Stroke

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Feb. 26, 2020

Ischemic stroke, which accounts for 75-80% of strokes, is a predominant cause morbidity and mortality worldwide. Recently, post-stroke immune response becomes new breakthrough the treatment strategy ischemic stroke. Glial cells, including microglia, astrocytes, oligodendrocytes, are major components peri-infarction environment in central nervous system have been elucidated to play critical roles regulation. However, increasing evidences suggest that glial cells exert different, even contrary effect Microglia, survey CNS homostasis regulate innate response, rapidly activated following The microglia would release inflammatory cytokines induce neuronal tissue injuries. On contrary, anti-inflammatory neurotrophic factors secreted by alternatively considered be benefit recovery Astrocytes activation reactive gliosis stroke contribute limitaion brain injury stabalize homeostasis. scar developed astrocytes also hinder reconnectivity extension. Oligodendrocytes shown extensively involved demyelination remyelination after Oligodendrocyte precursor able differentiate into reactived supposed lead functional recovery. Here we discuss mechanisms regulation mediated interaction between neurons. present review, from perspective various describes their possible at different stages future intervention targets.

Language: Английский

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Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 15, 2023

Abstract The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or “proteostasis”. quality control systems involve ER-associated degradation, chaperons, and autophagy. ER stress is activated when proteostasis broken with an accumulation of misfolded unfolded proteins in the ER. activates adaptive response to restore by initiating kinase R-like kinase, activating transcription factor 6, inositol requiring enzyme 1. multifaceted, acts on aspects at epigenetic level, including processing. Accumulated data indicates its key role homeostasis other diverse involved various ocular diseases, such glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, tumors, surface myopia. This review summarizes molecular mechanisms underlying aforementioned diseases from perspective. Drugs (chemicals, neurotrophic factors, nanoparticles), gene therapy, stem cell therapy are used treat alleviating stress. We delineate advancement targeting provide new treatment strategies diseases.

Language: Английский

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Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation

npj Regenerative Medicine, Journal Year: 2020, Volume and Issue: 5(1)

Published: Nov. 23, 2020

Mitochondria are fundamental for metabolic homeostasis in all multicellular eukaryotes. In the nervous system, mitochondria-generated adenosine triphosphate (ATP) is required to establish appropriate electrochemical gradients and reliable synaptic transmission. Notably, several mitochondrial defects have been identified central system disorders. Membrane leakage electrolyte imbalances, pro-apoptotic pathway activation, mitophagy among mechanisms implicated pathogenesis of neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's disease, well ischemic stroke. this review, we summarize pathways that contribute disease progression. Further, discuss pathological states damaged mitochondria impose on normal processes explore new therapeutic approaches diseases.

Language: Английский

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Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: March 30, 2021

Most cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry specifically mitochondria other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role the absence of remains elusive. Here, we demonstrate actively prevent packaging pro-inflammatory, oxidized would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, find distinction to be included damaged excluded is dependent on selective targeting one two distinct MDV pathways. We show Optic Atrophy 1 (OPA1) sorting nexin 9 (Snx9)-dependent MDVs required target EVs, while Parkinson's disease-related protein Parkin blocks this process by directing lysosomes. Our results provide insight interplay quality control mechanisms mitochondria-driven immune responses.

Language: Английский

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Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: July 27, 2020

Abstract Reactive astrocytes have been implicated in the pathogenesis of neurodegenerative diseases, including a non-cell autonomous effect on motor neuron survival ALS. We previously defined mechanism by which microglia release three factors, IL-1α, TNFα, and C1q, to induce neurotoxic astrocytes. Here we report that knocking out these factors markedly extends SOD1 G93A ALS mouse model, providing evidence for gliosis as potential therapeutic target.

Language: Английский

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Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases

Brain Behavior and Immunity, Journal Year: 2020, Volume and Issue: 91, P. 740 - 755

Published: Oct. 8, 2020

Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes microglia are the principal cells that mediate CNS. Pattern recognition receptors (PRRs), expressed by astrocytes microglia, sense pathogen-derived endogenous ligands released damaged initiate immune response. Toll-like (TLRs) a well-characterized family of PRRs. The contribution microglial TLR signaling to CNS pathology has been extensively investigated. Even though assume wide variety key functions, information about role astroglial TLRs disease injuries is limited. Because display heterogeneity exhibit phenotypic plasticity depending on effectors present local milieu, they can exert both detrimental beneficial effects. modulators these paradoxical properties. goal current review highlight played diseases. We discuss host defense as well dissemination viral bacterial infections examine link between pathogenesis diseases evidence showing pivotal influence sterile inflammation injury. Finally, we define research questions areas warrant further investigations context astrocytes, TLRs, dysfunction.

Language: Английский

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Neuroinflammation in Alzheimer’s Disease

Biomedicines, Journal Year: 2021, Volume and Issue: 9(5), P. 524 - 524

Published: May 7, 2021

Alzheimer's disease (AD) is a neurodegenerative associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise increasing age. There are currently no effective modifying treatments for AD, resulting in increasingly large socioeconomic personal costs. Increasing age an increase low-grade chronic inflammation (inflammaging) that may contribute the process AD. Although exact mechanisms remain unclear, aberrant elevation reactive oxygen nitrogen species (RONS) levels from several endogenous exogenous processes brain not only affect cell signaling, but also trigger cellular senescence, inflammation, pyroptosis. Moreover, compromised immune privilege allows infiltration peripheral cells infectious agents play role. Additionally, meta-inflammation as well gut microbiota dysbiosis drive neuroinflammatory process. Considering inflammatory/immune pathways dysregulated parallel cognitive dysfunction elucidating relationship between central nervous system facilitate development safe therapy We discuss some current ideas on inflammaging appear summarize details few immunomodulatory strategies being developed selectively target detrimental aspects neuroinflammation without affecting defense against pathogens tissue damage.

Language: Английский

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Neurotoxic Reactive Astrocytes Drive Neuronal Death after Retinal Injury

Cell Reports, Journal Year: 2020, Volume and Issue: 31(12), P. 107776 - 107776

Published: June 1, 2020

Glaucoma is a neurodegenerative disease that features the death of retinal ganglion cells (RGCs) in retina, often as result prolonged increases intraocular pressure. We show preventing formation neuroinflammatory reactive astrocytes prevents RGCs normally seen mouse model glaucoma. Furthermore, we these spared are electrophysiologically functional and thus still have potential value for function regeneration retina. Finally, demonstrate depends on combination both an injury to neurons presence astrocytes, suggesting may explain why toxic only some circumstances. Altogether, findings highlight drivers RGC chronic eye.

Language: Английский

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Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime?

Trends in Immunology, Journal Year: 2020, Volume and Issue: 41(9), P. 820 - 835

Published: Aug. 17, 2020

Language: Английский

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