Discovery of a brain-penetrant CHI3L1 inhibitor as an oral modulator of neuroinflammation in Alzheimers disease

Researchers have discovered a new compound called DELC2 that can inhibit a protein called CHI3L1 in the brain, a finding that could lead to new treatments for Alzheimer's disease. CHI3L1 is often found at higher levels in people with Alzheimer's, and its increased activity seems to contribute to glial dysfunction and inflammation.

Scientists screened a large library of compounds and identified DELC2 as one that can easily cross the brain's protective barrier. When they studied the molecular structure of DELC2, they found it fits into a specific pocket on CHI3L1, which blocks the protein's ability to interact with another protein called RAGE. This disruption lessens CHI3L1's role in triggering inflammatory responses and reduces the formation of abnormal proteins linked to Alzheimer's.

In laboratory tests using brain cells, DELC2 dampened the inflammatory signaling caused by CHI3L1, decreased the number of inflammatory microglia, and helped clear a harmful protein called amyloid-beta from the brain. When DELC2 was given orally to mice genetically engineered to develop Alzheimer's symptoms, it maintained a presence in the brain over time. This resulted in better memory performance, lower levels of various amyloid-beta forms, and decreased inflammation among both microglia and astrocytes.

By targeting the CHI3L1 glycan-recognition groove, DELC2 presents a promising avenue for developing therapies that specifically address the glial dysfunction and neuroinflammation underlying Alzheimer's disease.