Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Aug. 5, 2023

Microglia are the resident innate immune cells in brain with a major role orchestrating responses. They also provide frontline of host defense central nervous system (CNS) through their active phagocytic capability. Being professional phagocyte, microglia participate and autophagic clearance cellular waste debris as well toxic protein aggregates, which relies on optimal lysosomal acidification function. Defective microglial leads to impaired functions result perpetuation neuroinflammation progression neurodegeneration. Reacidification lysosomes has been shown reverse neurodegenerative pathology Alzheimer's disease. In this review, we summarize key factors mechanisms contributing impairment associated dysfunction microglia, how these defects contribute We further discuss techniques monitor pH therapeutic agents that can reacidify under disease conditions. Finally, propose future directions investigate lysosome-mitochondria crosstalk neuron-glia interaction for more comprehensive understanding its broader CNS physiological pathological implications.

Language: Английский

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Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 926 - 946

Published: Aug. 6, 2024

Language: Английский

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Roles of Oxidative Stress in Synaptic Dysfunction and Neuronal Cell Death in Alzheimer’s Disease

Antioxidants, Journal Year: 2023, Volume and Issue: 12(8), P. 1628 - 1628

Published: Aug. 17, 2023

Alzheimer’s disease (AD) is a brain disorder that progressively undermines memory and thinking skills by affecting the hippocampus entorhinal cortex. The main histopathological hallmarks of AD are presence abnormal protein aggregates (Aβ tau), synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, neuronal cell death. However, oxidative stress or damage also evident commonly overlooked considered consequence advancement dementia symptoms. control onset linked to activity amyloid-β peptide, which may serve as both antioxidant pro-oxidant molecules. Furthermore, correlated with proteins, nucleic acids, lipids in vulnerable populations, ultimately lead death through different molecular mechanisms. By recognizing an integral feature AD, alternative therapeutic preventive interventions developed tested potential complementary therapies for this devastating neurodegenerative disease.

Language: Английский

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Lysosomes in senescence and aging

EMBO Reports, Journal Year: 2023, Volume and Issue: 24(11)

Published: Oct. 9, 2023

Language: Английский

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Stress granules plug and stabilize damaged endolysosomal membranes

Nature, Journal Year: 2023, Volume and Issue: 623(7989), P. 1062 - 1069

Published: Nov. 15, 2023

Abstract Endomembrane damage represents a form of stress that is detrimental for eukaryotic cells 1,2 . To cope with this threat, possess mechanisms repair the and restore cellular homeostasis 3–7 also results in organelle instability by which stabilize damaged endomembranes to enable membrane remains unknown. Here, combining vitro cellulo studies computational modelling we uncover biological function granules whereby these biomolecular condensates rapidly at endomembrane sites act as plug stabilizes ruptured membrane. Functionally, demonstrate granule formation stabilization efficient endolysosomes, through both ESCRT (endosomal sorting complex required transport)-dependent independent mechanisms. We show blocking human macrophages creates permissive environment Mycobacterium tuberculosis , pathogen exploits survive within host.

Language: Английский

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Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: June 8, 2023

Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have linked to lysosomal de-acidification through impairing vacuolar-type ATPase ion channels on organelle membrane. Similar abnormalities are also present sporadic forms neurodegeneration, although underlying pathogenic mechanisms unclear remain be investigated. Importantly, recent studies revealed early occurrence impairment before onset neurodegeneration late-stage pathology. However, there is lack methods for pH monitoring vivo dearth lysosome-acidifying therapeutic agents. Here, we summarize evidence notion defective an indicator urge critical need technological advancement developing tools detection both clinical applications. We further discuss current preclinical pharmacological agents that modulate acidification, small molecules nanomedicine, their potential translation into lysosome-targeting therapies. Both timely development therapeutics restore function represent paradigm shifts targeting diseases.

Language: Английский

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Engineered mesenchymal stem cell-derived extracellular vesicles: A state-of-the-art multifunctional weapon against Alzheimer's disease

Theranostics, Journal Year: 2023, Volume and Issue: 13(4), P. 1264 - 1285

Published: Jan. 1, 2023

With the increase of population aging, number Alzheimer's disease (AD) patients is also increasing.According to current estimates, approximately 11% people over 65 suffer from AD, and that percentage rises 42% among 85.However, no effective treatment capable decelerating or stopping AD progression available.Furthermore, AD-targeted drugs composed synthetic molecules pose concerns regarding biodegradation, clearance, immune response, neurotoxicity.Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are essential intercellular communication mediators holding great promise as therapeutics owing their biocompatibility, versatility, effortless storage, superior safety, ability transport messenger noncoding RNAs, proteins, lipids, DNAs, other bioactive compounds derived cells.The functionalisation engineering strategies MSC-EVs highlighted (e.g.preconditioning, drug loading, surface modification, artificial EV fabrication), which could improve by multiple therapeutic effects, including clearing abnormal protein accumulation achieving neuroprotection immunomodulatory effects.Herein, this review summarises state-of-the-art engineer MSC-EVs, discusses progress in use therapeutics, presents perspectives challenges associated with related clinical applications, concludes engineered show immense potential therapy.

Language: Английский

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Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 24, 2023

Abstract Phospholipase D3 (PLD3) polymorphisms are linked to late-onset Alzheimer’s disease (LOAD). Being a lysosomal 5’-3’ exonuclease, its neuronal substrates remained unknown as well how defective nucleotide catabolism connects AD-proteinopathy. We identified mitochondrial DNA (mtDNA) major physiological substrate and show manifest build-up in lysosomes of PLD3-defective cells. mtDNA accretion creates degradative (proteolytic) bottleneck that presents at the ultrastructural level marked abundance multilamellar bodies, often containing remnants, which correlates with increased PINK1-dependent mitophagy. Lysosomal leakage cytosol activates cGAS–STING signaling upregulates autophagy induces amyloid precursor C-terminal fragment (APP-CTF) cholesterol accumulation. STING inhibition largely normalizes APP-CTF levels, whereas an APP knockout PLD3-deficient backgrounds lowers activation biosynthesis. Collectively, we demonstrate molecular cross-talks through feedforward loops between turnover, cGAS-STING metabolism that, when dysregulated, result endolysosomal demise observed LOAD.

Language: Английский

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Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 366, P. 712 - 731

Published: Jan. 21, 2024

Language: Английский

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Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy

Protein & Cell, Journal Year: 2024, Volume and Issue: unknown

Published: May 11, 2024

Abstract Alzheimer’s disease (AD), the leading cause of dementia, is characterized by accumulation amyloid plaques and neurofibrillary tangles in brain. This condition casts a significant shadow on global health due to its complex multifactorial nature. In addition genetic predispositions, development AD influenced myriad risk factors, including aging, systemic inflammation, chronic conditions, lifestyle, environmental exposures. Recent advancements understanding pathophysiology are paving way for enhanced diagnostic techniques, improved assessment, potentially effective prevention strategies. These discoveries crucial quest unravel complexities AD, offering beacon hope management treatment options millions affected this debilitating disease.

Language: Английский

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