Upadhyay, S.; Zhang, L.; Kaur, B.; Calvo-Barreiro, L.; Teplova, M.; Gabr, M.

Chitinase-3-like protein 1 (CHI3L1) is elevated in Alzheimers disease (AD), but its role in glial dysfunction and therapeutic tractability remain unclear. Here, screening a 4.2-billion-compound DNA-encoded library identified DELC2, a brain-penetrant CHI3L1 modulator. Biophysical and crystallographic studies showed that DELC2 binds the CHI3L1 glycan-recognition groove within an aromatic-hydrophobic pocket centered on Trp99 and Trp352. DELC2 inhibited CHI3L1-RAGE association, suppressed CHI3L1-induced inflammatory signaling, reduced Gal-3-positive microglia, and restored amyloid-{beta} uptake in glial cultures. In human cerebrospinal fluid, CHI3L1 was elevated in AD and correlated with astrocytic NF-{kappa}B activation. DELC2 phenocopied CHI3L1 immunodepletion, whereas CHI3L1 add-back restored inflammatory and amyloid-{beta}-handling defects. Oral DELC2 achieved sustained unbound brain exposure in 5xFAD mice, improved cognitive performance, reduced multiple amyloid-{beta} species, and attenuated astrocytic and microglial inflammatory programs. These findings establish the CHI3L1 glycan-recognition groove as a druggable regulator of RAGE-associated glial dysfunction and identify DELC2 as a chemical scaffold for CHI3L1-directed therapy in AD.