Journal of Neuroinflammation最新文献

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, synaptic dysfunction, and cognitive decline. Impairment of microglial autophagy-lysosomal pathway (ALP) is increasingly recognized as a key driver of the disease progression. Transcription factor EB (TFEB), a master regulator of ALP, has emerged as a promising therapeutic target; however, its specific role in microglia remains unclear. Here, we aimed to determine the therapeutic effects of microglial TFEB expression in AD pathogenesis. We established a tamoxifen-inducible, microglia-specific TFEB-overexpressing 5xFAD mouse line (5xTFEB) and conducted behavioural testing, histopathology and biochemical analyses, live-cell imaging of Aβ phagocytosis, and bulk RNA sequencing. Differential gene expressions were analysed, and inflammasome activation was evaluated. Microglial TFEB overexpression restored ALP function, promoted phagolysosomal clearance of oligomeric Aβ, and reduced the amyloid burden in the cortex, hippocampus, and entorhinal cortex of the 5xFAD mice. These changes rescued memory deficits in both male and female 5xTFEB mice. Transcriptomic profiling revealed upregulation of ALP and downregulation of inflammatory signalling. Additionally, inflammasome activation was attenuated in 5xTFEB mice. Targeted TFEB activation in microglia reprograms degradative and immune pathways, enhancing Aβ clearance while alleviating neuroinflammation and cognitive impairment in AD. Overall, microglial TFEB modulation is a promising cell-type-specific therapeutic strategy for AD and related neurodegenerative disorders.

Ischemic stroke remains a leading cause of global mortality and disability. While timely vascular recanalization is the most direct and clinically validated intervention for cerebral ischemia, reperfusion often induces secondary brain injury, with neuroinflammation playing a central role. Single-cell sequencing data from an ischemic stroke mouse model identify G protein-coupled receptor 35 (GPR35) as a potential regulator of post-ischemic inflammatory responses. GPR35 expression was markedly increased in both in vivo cerebral ischemia-reperfusion models and in vitro oxygen-glucose deprivation systems, predominantly localizing to microglia. Functional studies revealed that genetic knockdown of GPR35 in murine brain tissue significantly exacerbated cerebral infarction volume, neurological deficits, and neuroinflammation in animal models, whereas GPR35 overexpression produced therapeutic effects. Consistently, pharmacological activation of GPR35 using zaprinast attenuated ischemia-reperfusion injury and reduced proinflammatory cytokine production. Mechanistically, zaprinast-mediated GPR35 activation suppressed proinflammatory cytokine production via modulation of the Raf1/ERK1/2/MAPK signaling cascade. Notably, Raf1 knockdown attenuated the pathological exacerbation induced by GPR35 deficiency in peri-infarct regions. Co-immunoprecipitation analyses revealed a direct interaction between GPR35 and Raf1, with the CR2 domain, a critical region for Raf1 autoinhibition, identified as the primary binding interface. Collectively, these findings demonstrate that zaprinast confers cerebroprotective effects in cerebral ischemia-reperfusion injury by activating GPR35, ultimately attenuating infarct progression and neuroinflammation. This mechanistic insight positions GPR35 as a promising therapeutic target for mitigating reperfusion injury in ischemic stroke.