Peripheral cancer attenuates amyloid pathology in Alzheimer's disease via cystatin-c activation of TREM2.

Abstract

Alzheimer's disease (AD) and cancer are among the most devastating diseases worldwide. Epidemiological data indicate that the incidence of AD significantly decreases in patients with a history of cancer. However, whether and how peripheral cancer may affect AD progression is yet to be studied. Here, we find that peripheral cancer inhibits amyloid pathology and rescues cognition via secretion of cystatin-c (Cyst-C), which binds amyloid oligomers and activates triggering receptor expressed on myeloid cells 2 (TREM2) in microglia, enabling microglia to degrade the pre-existing amyloid plaques in AD mice. These effects of Cyst-C are abolished by a cell-type-specific deletion (Cx3cr1) or mutation of TREM2 (TREM2) or Cyst-C (Cyst-C) in microglia. Together, these findings provide significant conceptual advances into cancer neuroscience and establish therapeutic avenues that are distinct from the present amyloid-lowering strategies, aiming at degrading the existing amyloid plaques for precision-targeted AD therapy.