SUMO1 modulates A[beta] generation via BACE1 accumulation

Accumulation of disease-related proteins is a characteristic event observed in the pathogenesis of neurodegenerative diseases. [beta]-secretase (BACE)-1, which initiates generation of [beta]-amyloid (A[beta]), is increased in the Alzheimer's diseased brain. However, the mechanisms of BACE1 accumulation in Alzheimer's disease are largely unknown. In this report, we found that small ubiquitin-like modifier (SUMO)-1 interacts with the dileucine motif of BACE1 and regulates the level of BACE1 protein. This was proved by the coimmunoprecipitation, and gain or loss of function experiments. Altering 3 SUMO isoforms affects BACE1 protein levels, and consequently results in altered amyloid precursor protein processing and A[beta] generation. BACE1 levels were increased in response to A[beta] or apoptosis, but not in cells lacking SUMO1. A[beta] increased SUMO1 protein levels in rat cortical neurons. Moreover, SUMO1 immunoreactivity was increased in the amyloid precursor protein transgenic mice. Furthermore, the C-terminus fragments of BACE1 containing dileucine motif reduced A[beta] generation by SUMO1 overexpression. Our study indicates SUMO1 is not only a novel and potent regulator of BACE1 accumulation and A[beta] generation but also a potential therapeutic target for Alzheimer's disease.