The LDL Receptor-Related Protein 1: Mechanisms and roles in promoting Aβ efflux transporter in Alzheimer's disease

Weiyi Li; Canyu Chen; Bo Xu; Jixiang Chen; Mingxia Yang; Lili Gao; Jiecan Zhou

doi:10.1016/j.bcp.2024.116643

The LDL Receptor-Related Protein 1: Mechanisms and roles in promoting Aβ efflux transporter in Alzheimer's disease

Biochem Pharmacol. 2024 Nov 20:116643. doi: 10.1016/j.bcp.2024.116643. Online ahead of print.

Authors

Weiyi Li¹, Canyu Chen², Bo Xu², Jixiang Chen², Mingxia Yang¹, Lili Gao³, Jiecan Zhou⁴

Affiliations

¹ The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China.
² The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
³ The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
⁴ The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China. Electronic address: zhoujiecan@fsyy.usc.edu.cn.

PMID: 39577706
DOI: 10.1016/j.bcp.2024.116643

Abstract

The LDL Receptor-Related Protein 1(LRP1), a member of the Low-density Lipoprotein (LDL) receptor family, is a multifunctional cellular transporter and signaling receptor, this includes regulation of lipid metabolism, cell migration and signaling. Abnormal accumulation of amyloid beta (Aβ) in the brain is thought to be the main pathological change in Alzheimer's disease. By binding to a variety of ligands, LRP1 is involved in the internalization and degradation of Aβ, thereby affecting the course of Alzheimer's disease (AD). Here, we discuss the main mechanisms by which LRP1 mediates Aβ degradation and clearance and several current therapeutic approaches targeting LRP1. Finally we concluded that modulating the expression level of LRP1 is an effective way to attenuate Aβ deposition and ameliorate AD. Abbreviations: LRP1, LDL Receptor-Related Protein 1;LDL, Low Density Lipoprotein; Aβ, amyloid beta; AD, Alzheimer's disease; APP, amyloid precursor protein; ApoE, apolipoprotein E; TGF, growth factor; MMP, matrix metalloproteinase;TAT, thrombin-antithrombin complex; BBB, blood-brain barrier; MMP-9,cyclophilin A (CypA)-matrix metalloproteinase-9; VMC, Vascular Mural Cell; IDE,insulin degrading enzyme; EVs, extracellular vesicles; sLRP1,shed LRP1; BDNF, brain-derived neurotrophin; IGF-1,insulin-like growth factor 1; NGF, nerve growth factor; MAPK,mitogen-activated protein kinase; ERK1/2,exogenous signal-regulated kinase1/2;JNK, c-Jun amino-terminal kinase; TLR4, toll-like receptor 4; NF-κB,nuclear factor-κB; GCAP,guanylate cyclase-activating protein; KD, ketogenic diet;KB, ketone body; BLECs,Brain-like endothelial cell; BYHWD, Buyang Huanwu decoction; LGZG, Linguizhugan decoction;P- gp, P-glycoprotein;PPARγ, Peroxisome proliferator-activated receptor γ;SP16,SERPIN peptide 16; Asx, Astaxanthin; Bex, Bexarotene.

Keywords: Alzheimer’s disease; Aβ clearance; Endocytosis; LRP1; Targeted therapies.

Publication types

Review