CHI3L1/YKL-40 signaling inhibits neurogenesis in models of Alzheimer's disease.

CHI3L1/YKL-40 is an astrocyte-secreted glycoprotein recognized as a biomarker of CNS inflammation and implicated in Alzheimer's disease (AD) cognitive decline. However, its precise pathological role remains unclear. Here, we investigate CHI3L1's function and its therapeutic potential in AD using both human induced pluripotent stem cell-derived neurogenesis models and in vivo conditional AD mouse models, with astrocyte-specific CHI3L1 knockout, alongside 5XFAD mice. Our data reveal that CHI3L1 secretion by astrocytes impairs neural stem cell (NSC) proliferation and neuronal differentiation by activating the CRTH2 receptor, which triggers a downstream cascade involving IKKβ, S6K1, and S6 phosphorylation. This cascade depletes the NSC pool in the hippocampus, thereby reducing neurogenesis. Notably, targeting astrocytic CHI3L1 or blocking CRTH2 and its downstream effectors substantially restored neurogenesis and cognitive function, highlighting CHI3L1 as a promising therapeutic target for AD and related neurodegenerative disorders.