PT - JOURNAL ARTICLE AU - Tanokashira, Daisuke AU - Motoki, Kazumi AU - Minegishi, Seiji AU - Hosaka, Ai AU - Mamada, Naomi AU - Tamaoka, Akira AU - Okada, Takashi AU - Lakshmana, Madepalli K. AU - Araki, Wataru TI - LRP1 Downregulates the Alzheimer’s β-Secretase BACE1 by Modulating Its Intraneuronal Trafficking AID - 10.1523/ENEURO.0006-15.2015 DP - 2015 Mar 01 TA - eneuro PG - ENEURO.0006-15.2015 VI - 2 IP - 2 4099 - http://www.eneuro.org/content/2/2/ENEURO.0006-15.2015.short 4100 - http://www.eneuro.org/content/2/2/ENEURO.0006-15.2015.full SO - eneuro2015 Mar 01; 2 AB - The β-secretase called BACE1 is a membrane-associated protease that initiates the generation of amyloid β-protein (Aβ), a key event in Alzheimer’s disease (AD). However, the mechanism of intraneuronal regulation of BACE1 is poorly understood. Here, we present evidence that low-density lipoprotein receptor-related protein 1 (LRP1), a multi-functional receptor, has a previously unrecognized function to regulate BACE1 in neurons. We show that deficiency of LRP1 exerts promotive effects on the protein expression and function of BACE1, whereas expression of LRP-L4, a functional LRP1 mini-receptor, specifically decreases BACE1 levels in both human embryonic kidney (HEK) 293 cells and rat primary neurons, leading to reduced Aβ production. Our subsequent analyses further demonstrate that (1) both endogenous and exogenous BACE1 and LRP1 interact with each other and are colocalized in soma and neurites of primary neurons, (2) LRP1 reduces the protein stability and cell-surface expression of BACE1, and (3) LRP1 facilitates the shift in intracellular localization of BACE1 from early to late endosomes, thereby promoting lysosomal degradation. These findings establish that LRP1 specifically downregulates BACE1 by modulating its intraneuronal trafficking and stability through protein interaction and highlight LRP1 as a potential therapeutic target in AD.