Microglial cathepsin E plays a role in neuroinflammation and amyloid β production in Alzheimer's disease

Regulation of neuroinflammation and beta-amyloid (A beta) production are critical factors in the pathogenesis of Alzheimer's disease (AD). Cathepsin E (CatE), an aspartic protease, is widely studied as an inducer of growth arrest and apoptosis in several types of cancer cells. However, the function of CatE in AD is unknown. In this study, we demonstrated that the ablation of CatE in human amyloid precursor protein knock-in mice, called APP(NL-G-F) mice, significantly reduced A beta accumulation, neuroinflammation, and cognitive impairments. Mechanistically, microglial CatE is involved in the secretion of soluble TNF-related apoptosis-inducing ligand, which plays an important role in microglia-mediated NF-kappa B-dependent neuroinflammation and neuronal A beta production by beta-site APP cleaving enzyme 1. Furthermore, cannula-delivered CatE inhibitors improved memory function and reduced A beta accumulation and neuroinflammation in AD mice. Our findings reveal that CatE as a modulator of microglial activation and neurodegeneration in AD and suggest CatE as a therapeutic target for AD by targeting neuroinflammation and A beta pathology.

Automated summary

The regulation of neuroinflammation and beta-amyloid production is important in the development of Alzheimer's disease. In this study, it was found that the elimination of CatE significantly reduced A beta accumulation, neuroinflammation, and cognitive impairments. The findings suggest that CatE may be a therapeutic target for Alzheimer's disease.