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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Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 27, 2025

Abstract Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play central role. These immune cells undergo reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, HIF-1α orchestrating these processes. Microglial metabolism adapts environmental stimuli, shifting oxidative phosphorylation glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts an energy sensor, coordinating lipid glucose metabolism. TREM2 APOE regulate microglial homeostasis, influencing Aβ clearance responses. LPL ABCA7, both associated AD risk, modulate processing cholesterol transport, linking neurodegeneration. PPARG further supports by regulating inflammatory Amino acid also contributes function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked pathology. Additionally, glucose-6-phosphate dehydrogenase regulates pentose phosphate maintaining redox balance activation. Dysregulated metabolism, influenced genetic variants APOE4, impair responses exacerbate progression. Recent findings highlight interplay regulators like REV-ERBα, which modulates inflammation, Syk, influences clearance. insights offer promising therapeutic targets, including strategies aimed at modulation, could restore function depending on stage. By integrating metabolic, immune, factors, this review underscores importance of immunometabolism AD. Targeting pathways provide novel for mitigating restoring function, ultimately paving way innovative treatments neurodegenerative diseases.

Language: Английский

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Proteostasis and neurodegeneration: a closer look at autophagy in Alzheimer's disease

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Nov. 2, 2023

Alzheimer's disease (AD) is characterized by the accumulation of misfolded amyloid-beta and tau proteins. Autophagy acts as a proteostasis process to remove protein clumps, although it progressively weakens with aging AD, thus facilitating toxic proteins causing neurodegeneration. This review examines impact impaired autophagy on progression AD pathology. Under normal circumstances, removes abnormal damaged organelles, but any dysfunction in this can lead exacerbation amyloid pathology, particularly AD. There increasing attention therapeutic tactics revitalize autophagy, including reduced caloric intake, autophagy-stimulating drugs, genetic therapy. However, translation these strategies into clinical practice faces several hurdles. In summary, integrates understanding intricate role reinforces promising prospects beneficial target for treatments modify course disease.

Language: Английский

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Oxidative stress and inflammation cause auditory system damage via glial cell activation and dysregulated expression of gap junction proteins in an experimental model of styrene-induced oto/neurotoxicity

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Jan. 4, 2024

Abstract Background Redox imbalance and inflammation have been proposed as the principal mechanisms of damage in auditory system, resulting functional alterations hearing loss. Microglia astrocytes play a crucial role mediating oxidative/inflammatory injury central nervous system; however, glial cells is still elusive. Objectives Here we investigated glial-mediated responses to toxic peripheral structures pathway, i.e., cochlea cortex (ACx), rats exposed styrene, volatile compound with well-known oto/neurotoxic properties. Methods Male adult Wistar were treated styrene (400 mg/kg daily for 3 weeks, 5/days week). Electrophysiological, morphological, immunofluorescence molecular analyses performed both ACx evaluate underlying styrene-induced oto/neurotoxicity system. Results We showed that insult induced by increases oxidative stress ACx. This was associated macrophages cell activation, increased expression inflammatory markers (i.e., pro-inflammatory cytokines chemokine receptors) connexin (Cxs) pannexin (Panx) expression, likely responsible dysregulation microglia/astrocyte network. Specifically, found downregulation Cx26 Cx30 cochlea, high level Cx43 Panx1 Conclusions Collectively, our results provide novel evidence on immune activation system at levels, also involving gap junction networks. Our data suggest targeting connexin/pannexin might be useful attenuate

Language: Английский

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Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Age-related macular degeneration (AMD) is a prevalent degenerative disorder of the central retina, which holds global significance as fourth leading cause blindness. The condition characterized by multifaceted pathophysiology that involves aging, oxidative stress, inflammation, vascular dysfunction, and complement activation. complex interplay these factors contributes to initiation progression AMD. Current treatments primarily address choroidal neovascularization (CNV) in neovascular However, approval novel drug therapies for atrophic more gradual variant, known geographic atrophy (GA), has recently occurred. In light substantial impact AMD on affected individuals' quality life strain it places healthcare systems, there pressing need innovative medications. This paper aims provide an updated comprehensive overview advancements our understanding etiopathogenesis Special attention will be given influence aging altered redox status mitochondrial dynamics, cell death pathways, intricate between stress system, specifically context GA. Additionally, this review shed newly approved explore emerging alternative treatment strategies field. objective contribute ongoing dialogue surrounding AMD, offering insights into latest developments may pave way effective management intervention approaches.

Language: Английский

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Alkaloids as neuroprotectors: targeting signaling pathways in neurodegenerative diseases

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

Language: Английский

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A Comparative Study of a Potent CNS-Permeable RARβ-Modulator, Ellorarxine, in Neurons, Glia and Microglia Cells In Vitro

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3551 - 3551

Published: April 10, 2025

Vitamin A (retinol) and its derivatives (retinoids) assume critical roles in neural development, cellular differentiation, axon elongation, programmed cell apoptosis various fundamental processes. Retinoids function by binding to specific nuclear receptors, such as retinoic acid receptors (RARs) retinoid X (RXRs), activating signalling pathways the cells. The disruption of pathway can result neuroinflammation, oxidative ER stress mitochondrial dysfunction has been implicated a wide range neurodegenerative diseases. present study explored potential therapeutic application our innovative CNS-permeable synthetic retinoid, Ellorarxine, for treatment disorders vitro. An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay, lactate dehydrogenase (LDH) enzyme-linked immunosorbent assay (ELISA), immunocytochemistry immunofluorescence staining were performed. Ellorarxine increased Cyp26 and, selectively, RARβ protein expression neurons, glia microglia. significantly reduced death (neurons, glia), viability (neurons), modulated cytokine release (microglia), positively regulated autophagy glia, microglia). These results suggest that is promising drug candidate should be further investigated

Language: Английский

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Impaired Macroautophagy in Oligodendrocyte Precursor Cells Exacerbates Aging-related Cognitive Deficits via a Senescence Associated Signaling

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 21, 2024

Abstract Aging drives cognitive decline in the adult brain with unclear mechanisms. Previously, oligodendrocyte precursor cells (OPCs), source of myelin-forming central nervous system (CNS), have been linked to aging by their compromised differentiation and regeneration capability. Whether a myelination-independent function OPCs is involved remains unknown. In this study, we herein report novel role via disrupting neuronal plasticity. Our results demonstrate that macroautophagy influx declines aged OPCs, which accumulation senescent brains. Senescent impair plasticity exacerbate neurodegeneration CCL3/5-CCR5 signaling, eventually leading decline. for first time, demonstrates identifies declined autophagy driver aging-associated

Language: Английский

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Comparative Study of a Potent CNS-Permeable RARβ-Modulator, Ellorarxine, in Neuronal Cells In Vitro

Published: March 8, 2024

.Vitamin A (retinol) and its derivatives (retinoids) assume critical roles in neural development, cellular differentiation, axon elongation, programmed cell apoptosis various fundamental processes. Retinoids function by binding to specific nuclear receptors, such as retinoic acid receptors (RARs) retinoid X (RXRs), activating signaling pathways the cells. Disruption of pathway can result neuroinflammation, ox-idative stress, mitochondrial dysfunction neurodegenerative processes, has been asso-ciated with a range diseases. The present study explores potential therapeutic application our innovative synthetic retinoid, Ellorarxine, also known DC645 NVG0645, for treatment disorders vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay, lactate dehy-drogenase (LDH) enzyme-linked immunosorbent assay (ELISA), senescence-associated (SA) β-galactosidase (β-gal) staining immunofluorescence were performed. re-sults showed that no cytotoxicity was detected at experimental concentrations Ellorarxine. Ellorarxine significantly reduced death, increased viability, num-ber senescent cells, modulated cytokine release regulated autophagy. Furthermore, Cyp26 selectively RARβ expression. These results make promising drug candidate should be further investigated .

Language: Английский

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Exploring non-canonical targets in Alzheimer’s disease: a departure from the norm

The Egyptian Journal of Neurology Psychiatry and Neurosurgery, Journal Year: 2024, Volume and Issue: 60(1)

Published: Nov. 11, 2024

Abstract Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized by neurological impairments such as visual and sensory difficulties, motor dysfunction, sphincter issues, incoordination, gait abnormalities, cognitive decline. Despite advances in understanding AD pathophysiology the expansion of therapeutic options over past three decades, remains incurable. Current therapies, even those specifically targeting AD, often fail to significantly alter its progression, underscoring need for innovative treatment approaches beyond symptomatic relief. This calls re-examination pathology identify potential targets that go conventional strategies. review highlights four most promising non-canonical targets: oligodendrocytes, blood–brain barrier (BBB), neuroimmunometabolism, coagulation system. These components are crucial maintaining integrity proper function neurons brain, playing key roles progression AD. Oligodendrocytes, example, essential myelination neuronal support, while BBB dysfunction can lead impaired clearance toxic proteins. Neuroimmunometabolism offers insights into how metabolic processes influence immune responses brain dysregulation system has been linked increased neuroinflammation vascular abnormalities Recent discoveries these fields provide new avenues identifying targets. By exploring pathways, future research may offer breakthroughs treating moving management towards disease-modifying

Language: Английский

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