LRP1 Downregulates the Alzheimer's -Secretase BACE1 by Modulating Its Intraneuronal

The -secretase called BACE1is a membrane-associated protease that initiates the generation of amyloid -protein (A), a key event in Alzheimer’s disease (AD). However, the mechanism of intraneuronal regulation of BACE1is poorly understood. Here, we present evidence that low-density lipoprotein receptor-related protein1 ( LRP1), a multi-functional receptor, has a previously unrecognized function to regulate BACE1in neurons. We show that deficiency of LRP1exerts promotive effects on the protein expression and function of BACE1, whereas expression of LRP-L4, a functional LRP1mini-receptor, specifically decreases BACE1levels in both human embryonic kidney ( HEK) 293 cellsand rat primary neurons, leading to reduced A production. Our subsequent analyses further demonstrate that (1) both endogenous and exogenous BACE1and LRP1interact with each other and are colocalized in somaand neurites of primary neurons, (2) LRP1reduces the protein stability and cell-surface expression of BACE1, and (3) LRP1facilitates the shift in intracellular localization of BACE1from early to late endosomes, thereby promoting lysosomal degradation. These findings establish that LRP1specifically downregulates BACE1by modulating its intraneuronal trafficking and stability through protein interaction and highlight LRP1as a potential therapeutic target in AD.