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

Turning microglia neuroprotective: Towards connexin43-specific therapy of Alzheimer’s disease DOI Open Access
Yixun Su, Hui Li, Wei Zhang

и другие.

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

Процитировано

0
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

Процитировано

0