PT - JOURNAL ARTICLE AU - Daisuke Tanokashira AU - Kazumi Motoki AU - Seiji Minegishi AU - Ai Hosaka AU - Naomi Mamada AU - Akira Tamaoka AU - Takashi Okada AU - Madepalli K. Lakshmana AU - Wataru Araki TI - LRP1 down-regulates the Alzheimer’s β-secretase BACE1 by modulating its intraneuronal trafficking AID - 10.1523/ENEURO.0006-15.2015 DP - 2015 Apr 10 TA - eneuro PG - ENEURO.0006-15.2015 4099 - http://www.eneuro.org/content/early/2015/04/10/ENEURO.0006-15.2015.short 4100 - http://www.eneuro.org/content/early/2015/04/10/ENEURO.0006-15.2015.full 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 inhibitory 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 i) both endogenous and exogenous BACE1 and LRP1 interact with each other and are co-localized in soma and neurites of primary neurons, ii) LRP1 reduces the protein stability and cell-surface expression of BACE1, and iii) LRP1 facilitates the shift in intracellular localization of BACE1 from early to late endosomes, thereby promoting lysosomal degradation. These findings establish that LRP1 specifically down-regulates BACE1 by modulating its intraneuronal trafficking and stability through protein interaction and highlight LRP1 as a potential therapeutic target in AD. Significance Statement: The β-secretase called BACE1 is a membrane-associated protease that initiates the generation of amyloid β-protein, a key event in Alzheimer’s disease. However, the mechanism of inraneuronal regulation of BACE1 is poorly understood. We investigated this issue by focusing on the molecular relationship between BACE1 and low-density lipoprotein receptor-related protein 1 (LRP1), a multi-functional receptor. Our analyses revealed that LRP1 specifically down-regulates BACE1 protein expression in human embryonic kidney (HEK) 293 cells and rat primary neurons by facilitating its intracellular trafficking from early to late endosomes through protein interaction, thereby promoting lysosomal degradation. This study thus establishes that LRP1 plays a previously unrecognized role in negatively regulating BACE1 in neurons.