title: LRP1 Downregulates the Alzheimer's β-Secretase BACE1 by Modulating Its Intraneuronal Trafficking
abstract: 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.
authors.affiliation: Department of Demyelinating Disease and Aging, National Institute of Neuroscience , NCNP, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tanokashira
authors.affiliation: Department of Demyelinating Disease and Aging, National Institute of Neuroscience , NCNP, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Motoki
authors.affiliation: Department of Demyelinating Disease and Aging, National Institute of Neuroscience , NCNP, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Minegishi
authors.affiliation: Department of Demyelinating Disease and Aging, National Institute of Neuroscience , NCNP, Kodaira, Tokyo 187-8502, Japan ; Department of Neurology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Hosaka
authors.affiliation: Department of Demyelinating Disease and Aging, National Institute of Neuroscience , NCNP, Kodaira, Tokyo 187-8502, Japan ; Department of Neurology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Mamada
authors.affiliation: Department of Neurology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tamaoka
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.affiliation: Torrey Pines Institute for Molecular Studies , Port St. Lucie, Florida 34987-2352.
authors.forename: Madepalli K
authors.initials: MK
authors.lastname: Lakshmana
authors.affiliation: Department of Demyelinating Disease and Aging, National Institute of Neuroscience , NCNP, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Araki
keywords: Alzheimer’s disease; BACE1; LRP1; amyloid beta-protein; neuron