RT Journal Article SR Electronic T1 LRP1 Downregulates the Alzheimer’s β-Secretase BACE1 by Modulating Its Intraneuronal Trafficking JF eneuro JO eneuro FD Society for Neuroscience SP ENEURO.0006-15.2015 DO 10.1523/ENEURO.0006-15.2015 VO 2 IS 2 A1 Daisuke Tanokashira A1 Kazumi Motoki A1 Seiji Minegishi A1 Ai Hosaka A1 Naomi Mamada A1 Akira Tamaoka A1 Takashi Okada A1 Madepalli K. Lakshmana A1 Wataru Araki YR 2015 UL http://www.eneuro.org/content/2/2/ENEURO.0006-15.2015.abstract 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.