M1 muscarinic acetylcholine receptor interacts with BACE1 and regulates its proteosomal degradation

A prime culprit in the pathogenesis of Alzheimer's disease (AD) is overproduction/aggregation of β-amyloid (Aβ), which is derived from β-Amyloid Precursor Protein through sequential cleavages by β-site APP cleaving protein 1 (BACE1) and γ-secretase. The level/activity of BACE1 is elevated in sporadic AD and identification of proteins that affect BACE1 is important in AD research. Here we found that M1 Muscarinic acetylcholine receptor (M1 mAChR), an important G protein-coupled receptor involved in cholinergic neuronal activity, can interact with BACE1 and mediate its proteosomal degradation. Moreover, overexpression and downregulation of M1 mAChR can decrease and increase the levels of BACE1, as well as the generation of Aβ, respectively. These findings point to a novel coupling of BACE1 and M1 mAChR in AD and possibly schizophrenia.

► M1 mAChR interacts with BACE1. ► M1 mAChR mediates proteosomal degradation of BACE1. ► M1 mAChR affects Aβ generation through modulating the level of BACE1.