Neuroinflammation in Alzheimer disease

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

Опубликована: Дек. 9, 2024

Язык: Английский

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

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

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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, Год журнала: 2025, Номер 18(9)

Опубликована: Май 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

Язык: Английский

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Cholesterol Metabolism in Neurodegenerative Diseases

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

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

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

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

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

Опубликована: Ноя. 13, 2024

Язык: 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, 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

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

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

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

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

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Turning microglia neuroprotective: Towards connexin43-specific therapy of Alzheimer’s disease

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

Опубликована: Авг. 8, 2024

Abstract Alzheimer’s disease (AD) is the major cause of senile dementia without effective therapeutic strategies. The fundamental role microglia in AD pathology, particularly early stages, well acknowledged, although cell-specific targets were not identified. Here we show that microglial connexin 43 (Cx43) hemichannels controls reactivity AD, thus being a promising target. We discovered marked increase Cx43 protein periplaque post-mortem tissue from patients. Subsequently, using APP swe /PS1 dE9 mouse model demonstrated operating as influences function, which turn affects β-amyloid pathology. Ablation by genetic knockout shifted to neuroprotective phenotype, promoted microglia-plaque interaction while suppressing neurotoxic signature, thereby mitigating progression AD. Following this lead, developed novel formulation small molecule peptide, lipid nanoparticle-delivered TAT-Cx43 266-283 (TAT-CX43@LNPs), selectively blocks hemichannels. Our preclinical trial its efficacy delaying and rescuing β-amyloid-related neuropathology cognitive impairment mice. This study provides strong evidence progress our drug into clinical trials translate it disease-preventing (when administered stages) disease-modifying agents.

Язык: Английский

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