BMAL1-GPX3 axis in the choroid plexus mitigates Aβ pathology in an amyloid mouse model.

UNLABELLED: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with circadian rhythm disturbances strongly linked to its pathogenesis. The choroid plexus (ChP) is a circadian-regulated structure in the brain ventricles, but the role of the core clock gene brain and muscle ARNT-like protein 1 (BMAL1) in ChP in relation to AD pathology remains unclear. Here, we report that knockdown of Bmal1 in ChP epithelial cells of 5xFAD mice alleviates amyloid-β (Aβ) pathology, primarily by improving the function of astrocytes and border-associated macrophages (BAMs), with the latter potentially mediated by the upregulation of the secreted protein glutathione peroxidase 3 (GPX3), which reduces lipid peroxidation in BAMs. Collectively, our findings establish the ChP-driven BMAL1-GPX3 axis as a new Aβ clearance mechanism, with GPX3 representing a promising therapeutic target. These findings provide new mechanistic insights into AD and suggest innovative treatment approaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03691-9.