/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer's disease pathogenesis.

Regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer's disease (AD). YKL-40, a primarily astrocytic protein encoded by the gene , is a widely studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of /YKL-40 in AD is unknown. In a cohort of patients with AD, we observed that a variant in the human gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression. At baseline, deletion in mice had no effect on astrocyte activation while modestly promoting microglial activation. In a mouse APP/PS1 model of AD, deletion decreased amyloid plaque burden and increased periplaque expression of the microglial lysosomal marker CD68, suggesting that may suppress glial phagocytic activation and promote amyloid accumulation. Accordingly, knockdown increased phagocytosis of zymosan particles and of β-amyloid peptide in both astrocytes and microglia in vitro. We further observed that expression of is regulated by the circadian clock, as deletion of the core clock proteins BMAL1 or CLOCK/NPAS2 strongly suppresses basal expression, whereas deletion of the negative clock regulators PER1/PER2 increased expression. Basal mRNA was nonrhythmic because of a long mRNA half-life in astrocytes. However, inflammatory induction of was gated by the clock. Our findings reveal /YKL-40 as a modulator of glial phagocytic activation and AD pathogenesis in both mice and humans and suggest that the astrocyte circadian clock regulates inflammatory induction.