25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation DOI Creative Commons
Johnathan Romero, Danira Toral-Ríos, Jinsheng Yu

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 19, 2024

Abstract Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers neuroinflammation 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, hydroxylates form 25-hydroxycholesterol (25HC). 25HC can be further metabolized 7α,25-dihydroxycholesterol, which potent chemoattractant for leukocytes. We have previously shown that increases production secretion cytokine, IL-1β, by primary treated with lipopolysaccharide (LPS). In present study, wildtype (WT) Ch25h-knockout (CKO) mice were peripherally administered LPS induce state brain. LPS-treated WT mice, expression levels increased relative vehicle-treated mice. WT females produced significantly higher showed transcriptomic changes reflecting cytokine leukocyte migration than male However, similar males among CKO Ch25h-deficiency coincided decreased microglial activation systemic LPS. Proinflammatory intra-parenchymal infiltration leukocytes lower compared Amounts IL-1b IL-6 strongly correlated levels. Our results suggest role following peripheral administration

Язык: Английский

Neuroinflammation in Alzheimer disease DOI
Wiesje M. van der Flier, Wiesje M. van der Flier,

Frank Jessen

и другие.

Nature reviews. Immunology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Язык: Английский

Процитировано

16
Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications DOI Creative Commons
Sijia He, Ziying Xu, Xianlin Han

и другие.

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 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

Язык: Английский

Процитировано

2
25-Hydroxycholesterol modulates microglial function and exacerbates Alzheimer’s disease pathology: mechanistic insights and therapeutic potential of cholesterol esterification inhibition DOI Creative Commons
Hayoung Choi,

Haeng Jun Kim,

Sang‐Eun Lee

и другие.

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Фев. 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.

Язык: Английский

Процитировано

0
Intrahippocampal delivery of hyperphosphorylated human tau oligomers induces neurodegeneration in non-transgenic wildtype mice DOI Open Access
Hong‐Ru Chen,

Hsiao-Tien Hagar,

Kuan-Wei Wang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 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.

Язык: Английский

Процитировано

0
Metabolomic profiling identifies signatures and biomarkers linking air pollution to dementia risk: a prospective cohort study DOI
Fei Tian,

Yuhua Wang,

Zhenhe Huang

и другие.

Journal of Hazardous Materials, Год журнала: 2024, Номер 480, С. 136498 - 136498

Опубликована: Ноя. 13, 2024

Язык: Английский

Процитировано

3
Cholesterol Metabolism in Neurodegenerative Diseases DOI

Keqiang He,

Zhiwei Zhao,

Juan Zhang

и другие.

Antioxidants and Redox Signaling, Год журнала: 2024, Номер unknown

Опубликована: Июнь 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.

Язык: Английский

Процитировано

2
25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation DOI Creative Commons
Johnathan Romero, Danira Toral-Ríos, Jinsheng Yu

и другие.

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Окт. 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

Язык: Английский

Процитировано

2
Cell autonomous microglia defects in a stem cell model of frontotemporal dementia DOI Creative Commons
Abhirami K. Iyer, Lisa Vermunt, Farzaneh S. Mirfakhar

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 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

Язык: Английский

Процитировано

1
Heme Oxygenase‐1 Overexpression Activates the IRF1/DRP1 Signaling Pathway to Promote M2‐Type Polarization of Spinal Cord Microglia DOI Open Access
Wenping Lin, Ziming Cai,

Jinzhu Liang

и другие.

Drug Development Research, Год журнала: 2024, Номер 85(8)

Опубликована: Дек. 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.

Язык: Английский

Процитировано

1
25-hydroxycholesterol dysregulates brain endothelial cell function and exacerbates cerebral haemorrhage DOI Creative Commons
Víctor S. Tapia,

Sarah E. Withers,

Ran Zhou

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 10, 2024

Abstract The antiviral enzyme cholesterol 25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC), which modulates metabolism during infection, have been previously associated with vascular pathology. Viral infections linked to risk of intracerebral haemorrhage (ICH) but the molecular mechanisms leading brain vessel rupture via responses remain unknown. We hypothesised that CH25H/25HC pathway may impact neuroendothelial integrity in context infection-associated ICH. Here, using a SARS-CoV-2-spike-induced zebrafish ICH model foetal human SARS-CoV-2-associated cortical tissue containing microbleeds, we identified an upregulation CH25H cerebral haemorrhage. Using models endothelial cells, asked whether 25HC promote neurovascular dysfunction by modulating metabolism. found pharmacological inhibition HMGCR atorvastatin interacted exacerbate bleeding larvae vitro dysfunction. In 25HC-induced was also rescued supplementation. These results demonstrate factor can dysregulate function remodelling propose represents important component pathophysiology infection dysregulation Summary Statement dysregulates metabolism, thereby providing mechanistic link between viral conditions such as

Язык: Английский

Процитировано

0