Low-Density Lipoprotein Receptor-Related Protein-1 (LRP1) C4408R Mutant Promotes Amyloid Precursor Protein (APP) α-Cleavage in Vitro

Abstract

Previous studies have demonstrated that the low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) plays conflicting roles in Alzheimer’s disease (AD) pathogenesis, clearing β-amyloid (Aβ) from the brain while also enhancing APP endocytosis and resultant amyloidogenic processing. We have recently discovered that coexpression of mutant LRP1 C-terminal domain (LRP1-CT C4408R) with Swedish mutant amyloid precursor protein (APPswe) in Chinese hamster ovary (CHO) cells decreases Aβ production, while also increasing sAPPα and APP α-C-terminal fragment (α-CTF), compared with CHO cells expressing APPswe alone. Surprisingly, the location of this mutation on LRP1 corresponded with the α-secretase cleavage site of APP. Further experimentation confirmed that in CHO cells expressing APPswe or wild-type APP (APPwt), coexpression of LRP1-CT C4408R decreases Aβ and increases sAPPα and α-CTF compared with coexpression of wild-type LRP1-CT. In addition, LRP1-CT C4408R enhanced the unglycosylated form of LRP1-CT and reduced APP endocytosis as determined by flow cytometry. This finding identifies a point mutation in LRP1 which slows LRP1-CT-mediated APP endocytosis and amyoloidogenic processing, while enhancing APP α-secretase cleavage, thus demonstrating a potential novel target for slowing AD pathogenesis.

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease

“…Recent studies have identified numerous proteins that can regulate APP processing by modulating protein trafficking. For example, low-density lipoprotein receptor-related protein 1 (LRP1), an AD risk factor, is able to enhance APP endocytosis, leading to increased Aβ and sAPPβ generation [ 41 ], whereas mutation of LRP1 increases sAPPα secretion in vitro [ 42 , 43 ]. Another AD risk factor sortilin-related receptor containing LDLR A repeats (SORLA) can bind and sequester APP in intracellular compartments to reduce Aβ production [ 44 ].…”

Neuropathogenesis-on-chips for neurodegenerative diseases

“…In addition, this abnormal aggregation is induced by the impairment of protein regulation systems, such as the endoplasmic reticulum system, ubiquitin-proteasome system (UPS), and autophagy-lysosomal pathway (ALP) 69 . Importantly, dysfunction of several regulating proteins, such as LRP1 70 , SNX6 71 , GGA3 72 , and SORLA 73 affect APP endocytosis, endosomal trafficking, and Aβ production, which are closely associated with the onset of AD.…”