Neuroinflammation in Alzheimer disease

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

Language: Английский

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Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications

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

Published: Jan. 27, 2025

Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to involvement of lipid dysregulation in development AD. Nevertheless, precise lipidomic landscape and mechanistic roles lipids pathology remain poorly understood. This review aims highlight significance lipidomics lipid-targeting approaches diagnosis We summarized connection between human brain AD at both genetic species levels. briefly introduced technologies discussed potential challenges areas future advancements field for research. To elucidate central role converging multiple pathological aspects AD, we reviewed current knowledge on interplay major features, including amyloid beta, tau, neuroinflammation. Finally, assessed progresses obstacles lipid-based therapeutics proposed strategies leveraging

Language: Английский

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25-Hydroxycholesterol modulates microglial function and exacerbates Alzheimer’s disease pathology: mechanistic insights and therapeutic potential of cholesterol esterification inhibition

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 25, 2025

This study investigates the role of 25-hydroxycholesterol (25HC), a metabolite produced by cholesterol hydroxylase encoded Ch25h gene, in modulating microglial function and its potential implications Alzheimer's disease (AD) pathology. We demonstrated that 25HC impairs surveillance, reduces phagocytic capacity, increases production pro-inflammatory cytokines. In vivo two-photon microscopy revealed administration diminishes response to brain lesions, while flow cytometry confirmed reduced phagocytosis both vitro models. Additionally, amyloid-beta (Aβ) was shown upregulate expression elevate levels microglia, exacerbating these functional impairments. Mechanistically, found enhance esterification, disrupt cell membrane dynamics, further reduce mobility phagocytosis. Treatment with Avasimibe, esterification inhibitor, restored dynamics function, leading attenuated AD pathology 5XFAD mouse model. These findings suggest 25HC-induced changes contribute progression, targeting metabolism could offer therapeutic potential.

Language: Английский

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Intrahippocampal delivery of hyperphosphorylated human tau oligomers induces neurodegeneration in non-transgenic wildtype mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Hyperphosphorylated tau (p-tau) forms neurofibrillary tangles, a key biomarker for Alzheimer's disease and additional neurodegenerative tauopathies. However, tangles are not sufficient to cause neuronal dysfunction or death. Intrahippocampal injection of isolated from AD patients has limited effects on the cognitive functions non-transgenic mice, despite recapitulation pathological deposits in mouse brain. It therefore remains uncertain as whether all hyperphosphorylated is directly responsible neurodegeneration. We examined this issue by injecting recombinant p-tau oligomers hippocampus non-transgenic, wildtype mice found progressive deficits that correlate with neuron death spreading ipsilateral cortex. Apomorphine, which retards aggregation cytotoxicity vitro , antagonized p-tau-induced These results suggest pathogenic role novel model facilitating drug development.

Language: Английский

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The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation

Disease Models & Mechanisms, Journal Year: 2025, Volume and Issue: 18(9)

Published: May 23, 2025

ABSTRACT The antiviral enzyme cholesterol 25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC), which modulates metabolism during infection, have been associated with vascular pathology. Viral infections linked to intracerebral haemorrhage (ICH) risk, but the molecular mechanisms leading ICH via responses remain unknown. We hypothesised that CH25H/25HC pathway impacts neuroendothelial integrity in context of infection-associated ICH. Using a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-induced zebrafish model foetal human SARS-CoV-2-associated cortical tissue containing microbleeds, we identified upregulation CH25H cerebral haemorrhage. models brain endothelial cells, asked whether 25HC promotes neurovascular dysfunction by modulating metabolism. found pharmacological inhibition synthesis had an additive effect exacerbate bleeding vitro dysfunction. 25HC-induced was also rescued supplementation vitro. These results demonstrate can dysregulate function remodelling propose plays important role pathophysiology vessel infection dysregulation

Language: Английский

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Cholesterol Metabolism in Neurodegenerative Diseases

Antioxidants and Redox Signaling, Journal Year: 2024, Volume and Issue: unknown

Published: June 6, 2024

Cholesterol plays a crucial role in the brain, where it is highly concentrated and tightly regulated to support normal brain functions. It serves as vital component of cell membranes, ensuring their integrity, acts key regulator various processes. Dysregulation cholesterol metabolism has been linked impaired function onset neurodegenerative diseases such Alzheimer's disease (AD), Parkinson's disease, Huntington's disease.

Language: Английский

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25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation

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

Published: Oct. 5, 2024

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers neuroinflammation and, response to different inflammatory stimuli, overexpress a proinflammatory signature genes. Among these, Ch25h is gene overexpressed brain tissue from Alzheimer's disease as well various mouse models neuroinflammation. encodes cholesterol 25-hydroxylase, an enzyme upregulated activated microglia under conditions neuroinflammation, that hydroxylates form 25-hydroxycholesterol (25HC). 25HC can be further metabolized 7α,25-dihydroxycholesterol, which potent chemoattractant leukocytes. We have previously shown increases production secretion cytokine, IL-1β, by primary treated with lipopolysaccharide (LPS). In present study, wildtype (WT) Ch25h-knockout (KO) mice were peripherally administered LPS induce state brain. LPS-treated WT mice, expression levels increased relative vehicle-treated mice. females produced significantly higher showed transcriptomic changes reflecting cytokine leukocyte migration than male However, similar males among KO Ch25h-deficiency coincided decreased microglial activation systemic LPS. Proinflammatory intra-parenchymal infiltration leukocytes lower compared Amounts IL-1β IL-6 strongly correlated levels. Our results suggest role for following peripheral administration

Language: Английский

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Metabolomic profiling identifies signatures and biomarkers linking air pollution to dementia risk: a prospective cohort study

Journal of Hazardous Materials, Journal Year: 2024, Volume and Issue: 480, P. 136498 - 136498

Published: Nov. 13, 2024

Language: Английский

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Cell autonomous microglia defects in a stem cell model of frontotemporal dementia

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

Published: May 16, 2024

Neuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across diseases, there is strong evidence for active involvement immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that tau mRNA and protein are expressed human brains induced pluripotent stem cell (iPSC)-derived (iMGLs). Using iMGLs harboring the

Language: Английский

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Heme Oxygenase‐1 Overexpression Activates the IRF1/DRP1 Signaling Pathway to Promote M2‐Type Polarization of Spinal Cord Microglia

Drug Development Research, Journal Year: 2024, Volume and Issue: 85(8)

Published: Dec. 1, 2024

Microglia-mediated neuroinflammatory responses have a critical function in the spinal cord injury (SCI) mechanism, and targeted modulation of microglia activity has emerged as new therapeutic strategy for SCI. Heme oxygenase 1(HO-1) regulates close dynamic crosstalk between oxidative stress inflammatory responses. This investigation aimed to study molecular pathways by which HO-1 response microglia. We cultivated primary rat BV2 cell lines used lipopolysaccharide (LPS) stimulate establish an vitro model. The adeno-associated virus (AAV) was induce overexpression observe effects on survival, morphological changes, activation, cytokines secretion, mitochondrial dynamics, nucleotide-binding oligomerization domain-like receptor protein (NLRP3) complex nuclear factor-κB (NF-κB) signaling pathways. It found that successfully induced using AAV vitro. increased survival reduced apoptosis microenvironment. Overexpressed inhibited M1-type polarization, downregulated NF-κB pathway, NLRP3 secretion factors. maintained stability dynamics excessive cleavage. Further experiments showed activated interferon regulatory factor 1 (IRF1)/dynamin-related (DRP1) thereby promoting M2-type polarization improving neuronal survival. demonstrates activates IRF1/DRP1 axis, M2 attenuating neuroinflammation suppressing pathway. These outcomes offer visions important clues effectively managing SCI clinic.

Language: Английский

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