Mitofilin–mtDNA Axis Mediates Chronic Lead Exposure-Induced Synaptic Plasticity Impairment of Hippocampal and Cognitive Deficits

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 272 - 272

Published: Feb. 12, 2025

Neurotoxic damage resulting from lead pollution exposure constitutes a significant public health concern. The regulatory impact of (Pb) on neuronal dendritic spine plasticity, crucial mechanism for adaptation, warrants further investigation. To elucidate the role and Mitofilin-mtDNA axis in hippocampal synaptic plasticity learning memory impairment induced by exposure, this study, both vivo vitro models were subjected to chronic exposure. results showed that spatial abilities lead-exposed mice significantly reduced. Furthermore, Western blotting RT-PCR analyses demonstrated down-regulation expression mitochondrial inner membrane protein Mitofilin. Extended has potential compromise spines within CA1 region neurons disrupt structural integrity mitochondria. was associated with elevated levels malondialdehyde (MDA) reactive oxygen species (ROS) neurons. study additionally overexpression Mitofilin ameliorated deficits This also facilitated normal formation spines, preserved membrane, mitigated damage. revealed markedly suppressed release DNA (mtDNA) while concurrently reducing inflammasome Nlrp3 inflammatory cytokine IL-1β. Additionally, there reduction overexpression. These findings suggest may play mediating following through regulation function.

Language: Английский

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Deciphering motor dysfunction and microglial activation in mThy1-α-synuclein mice: a comprehensive study of behavioral, gene expression, and methylation changes

Frontiers in Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 18

Published: Feb. 13, 2025

Introduction Growing recognition of microglia’s role in neurodegenerative disorders has accentuated the need to characterize microglia profiles and their influence on pathogenesis. To understand changes observed microglial profile during progression synucleinopathies, gene expression DNA methylation were examined mThy1- α -synuclein mouse model. Methods Disease was determined using behavioral tests evaluating locomotor deficits before RNA extraction at 7 10 months from isolated for enzymatic methyl-sequencing RNA-sequencing. Results Pathway analysis these indicates a pro-inflammatory terms related synaptic maintenance. Expression both included regarding mitochondrial metabolic stress. While behavior symptoms progressed months, we see many previously activated pathways being inhibited later stage, with only 8 53 shared predicted be directionally concordant. Despite difference pathway directionality, 21 22 genes that differentially expressed annotated methylated regions had conserved directionality changes. Discussion These results highlight critical period disease progression, which respond -synuclein, suggesting transition early late stages disease.

Language: Английский

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Engrams across diseases: Different pathologies – unifying mechanisms?

Neurobiology of Learning and Memory, Journal Year: 2025, Volume and Issue: unknown, P. 108036 - 108036

Published: Feb. 1, 2025

Language: Английский

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Role of glial cells in neurotoxicological effects of alcohol

Advances in neurotoxicology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Three-photon in vivo imaging of neurons and glia in the medial prefrontal cortex with sub-cellular resolution

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: May 23, 2025

Abstract The medial prefrontal cortex (mPFC) is important for higher cognitive functions, including working memory, decision making, and emotional control. In vivo recordings of neuronal activity in the mPFC have been achieved via invasive electrical optical approaches. Here we apply low three-photon imaging mouse at unprecedented depth. Specifically, measure astrocytic Ca 2+ -transient parameters awake head-fixed mice up to a depth 1700 µm. Furthermore, longitudinally record dendritic spine density (0.41 ± 0.07 µm −1 ) deeper than 1 mm week. Using 1650 nm wavelength excite red fluorescent microglia, quantify their processes’ motility (58.9 2% turnover rate) previously unreachable depths (1100 µm). We establish enabling glial with subcellular resolution that will pave way novel discoveries this brain region.

Language: Английский

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Control of hippocampal synaptic plasticity by microglia–dendrite interactions depends on genetic context in mouse models of Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 20(1), P. 601 - 614

Published: Sept. 27, 2023

Abstract INTRODUCTION Human data suggest susceptibility and resilience to features of Alzheimer's disease (AD) such as microglia activation synaptic dysfunction are under genetic control. However, causal relationships between these processes, how genomic diversity modulates them remain systemically underexplored in mouse models. METHODS AD‐vulnerable hippocampal neurons were virally labeled inbred (C57BL/6J) wild‐derived (PWK/PhJ) APP/PS1 wild‐type mice, brain depleted from 4 8 months age. Dendrites assessed for synapse plasticity changes by evaluating spine densities morphologies. RESULTS In C57BL/6J, depletion blocked amyloid‐induced density morphology changes. At a finer scale, on individual branches was dependent microglia–dendrite physical interactions. Conversely, synapses PWK/PhJ mice showed remarkable stability response amyloid, no evidence contact‐dependent dendrites. DISCUSSION These results demonstrate that microglia‐dependent alterations specific projection pathways differentially controlled context.

Language: Английский

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Intercellular Adhesion Molecule 1 (ICAM-1): An Inflammatory Regulator with Potential Implications in Ferroptosis and Parkinson’s Disease

Cells, Journal Year: 2024, Volume and Issue: 13(18), P. 1554 - 1554

Published: Sept. 15, 2024

Intercellular adhesion molecule 1 (ICAM-1/CD54), a transmembrane glycoprotein, has been considered as one of the most important molecules during leukocyte recruitment. It is encoded by ICAM1 gene and plays central role in inflammation. Its crucial many inflammatory diseases such ulcerative colitis rheumatoid arthritis are well established. Given that neuroinflammation, underscored microglial activation, key element neurodegenerative Parkinson’s disease (PD), we investigated whether ICAM-1 this progressive neurological condition and, if so, to elucidate underpinning mechanisms. Specifically, were interested potential interaction between ICAM-1, glial cells, ferroptosis, an iron-dependent form cell death recently implicated PD. We conclude there exist direct indirect (via cells T cells) influences on ferroptosis further elucidation these interactions can suggest novel intervention for devastating disease.

Language: Английский

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Primary cortical cell tri-culture to study effects of amyloid-β on microglia function and neuroinflammatory response

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 5, 2024

Microglia play a critical role in neurodegenerative disorders, such as Alzheimer's disease, where alterations microglial function may result pathogenic amyloid-β (Aβ) accumulation, chronic neuroinflammation, and deleterious effects on neuronal function. However, studying these complex factors vivo, numerous confounding processes exist, is challenging, until recently, vitro models have not allowed sustained culture of cell types the same culture.

Language: Английский

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Genetic context controls early microglia-synaptic interactions in mouse models of Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 29, 2023

ABSTRACT Common features of Alzheimer’s disease (AD) include amyloid pathology, microglia activation and synaptic dysfunction, however, the causal relationships amongst them remains unclear. Further, human data suggest susceptibility resilience to AD neuropathology is controlled by genetic context, a factor underexplored in mouse models. To this end, we leveraged viral strategies label an AD-vulnerable neuronal circuit CA1 dendrites projecting frontal cortex genetically diverse C57BL/6J (B6) PWK/PhJ (PWK) APP/PS1 strains used PLX5622 non-invasively deplete brain microglia. Reconstructions labeled neurons revealed microglia-dependent changes dendritic spine density morphology B6 wild-type (WT) yet marked stability spines across PWK mice. We further showed that depend on direct microglia-dendrite interactions B6. but not PWK. Collectively, these results demonstrate alterations specific projection pathway are differentially context.

Language: Английский

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Regional Microglial Response in Enthorino-hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 12, 2024

Microglia and astrocytes are essential in sustaining physiological networks on the central nervous system, with their ability to remodel extracellular matrix, being pivotal for synapse plasticity. Recent findings challenge traditional view of homogenous glial populations brain, uncovering morphological, functional molecular heterogeneity among cells. This di-versity has significant implications both pathological brain states. In present study, we mechanically induced a Schaffer collateral lesion (SCL) mouse enthori-no-hippocampal slice cultures investigate behavior, i.e., microglia astrocytes, under metalloproteinases (MMPs) modulation lesioned area, CA3, denervated region, CA1. We observed distinct response patterns 3 days after lesion. Notably, GFAP-expressing showed no immediate changes post-SCL. re-sponses varied depending anatomical location. The MMPs inhibitor GM6001 did not affect microglial reactions while increasing Iba1 cells numbers CA1, underscoring complexity hippocampal neuroglial network post-injury. These highlight importance understanding regionalization following neural injury modulation, pave way further research into glia-targeted therapeutic strategies neurodegen-erative disorders.

Language: Английский

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