Targeting astrocytes in AD
Astrocytes and microglia play a dual role in Alzheimer’s disease (AD), increasing neuroinflammation and limiting plaque growth through phagocytic activity. The astrocytic protein YKL-40 is increased in the cerebrospinal fluid (CSF) of patients with AD; however, its role in AD pathophysiology is unclear. Here, Lananna et al. used mouse model and in vitro systems to show that Chi3l1, the gene coding for YKL-40, plays a detrimental role in AD. Its deletion reduced amyloid plaque formation and promoted Aβ phagocytosis. A polymorphism in CHI3L1 resulting in reduced protein expression was associated with slower AD progression in patients. The results suggest that YKL-40 could be targeted for reducing AD progression in patients.
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 Chi3l1, is a widely studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of Chi3l1/YKL-40 in AD is unknown. In a cohort of patients with AD, we observed that a variant in the human CHI3L1 gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression. At baseline, Chi3l1 deletion in mice had no effect on astrocyte activation while modestly promoting microglial activation. In a mouse APP/PS1 model of AD, Chi3l1 deletion decreased amyloid plaque burden and increased periplaque expression of the microglial lysosomal marker CD68, suggesting that Chi3l1 may suppress glial phagocytic activation and promote amyloid accumulation. Accordingly, Chi3l1knockdown increased phagocytosis of zymosan particles and of β-amyloid peptide in both astrocytes and microglia in vitro. We further observed that expression of Chi3l1 is regulated by the circadian clock, as deletion of the core clock proteins BMAL1 or CLOCK/NPAS2 strongly suppresses basal Chi3l1 expression, whereas deletion of the negative clock regulators PER1/PER2 increased Chi3l1 expression. Basal Chi3l1 mRNA was nonrhythmic because of a long mRNA half-life in astrocytes. However, inflammatory induction of Chi3l1 was gated by the clock. Our findings reveal Chi3l1/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 Chi3l1 induction.