AP-2 reduces amyloidogenesis by promoting BACE1 trafficking and degradation in neurons

ABSTRACT: Cleavage of amyloid precursor protein (APP) by BACE-1 (?-site APP cleaving enzyme-1) is the rate-limiting step in amyloid-? (A?) production and a neuropathological hallmark of Alzheimer's disease (AD). Despite decades of research, mechanisms of amyloidogenic APP processing remain highly controversial. Here, we show that in neurons APP processing and A? production are controlled by the protein complex-2 (AP-2), an endocytic adaptor known to be required for APP endocytosis. Now we find that AP-2 prevents amyloidogenesis by additionally functioning downstream of BACE1 endocytosis, regulating BACE1 endosomal trafficking and its delivery to lysosomes. AP-2 is decreased in iPSC-derived neurons from patients with late-onset AD, while conditional AP-2 knockout (KO) mice exhibit increased A? produc

SUBMITTER: Dr. Natalia, L. Kononenko 

PROVIDER: S-SCDT-EMBOR-2019-47954V1 | biostudies-other |

REPOSITORIES: biostudies-other