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Low-Density Lipoprotein Receptor-Related Protein-1 (LRP1) C4408R Mutant Promotes Amyloid Precursor Protein (APP) α-Cleavage in Vitro.
- Source :
-
Neuromolecular medicine [Neuromolecular Med] 2017 Sep; Vol. 19 (2-3), pp. 300-308. Date of Electronic Publication: 2017 Jun 13. - Publication Year :
- 2017
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Abstract
- Previous studies have demonstrated that the low-density lipoprotein 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 co-expression 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), co-expression of LRP1-CT C4408R decreases Aβ and increases sAPPα and α-CTF compared with co-expression 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 amyloidogenic processing, while enhancing APP α-secretase cleavage, thus demonstrating a potential novel target for slowing AD pathogenesis.
- Subjects :
- Alzheimer Disease genetics
Amyloid Precursor Protein Secretases metabolism
Amyloid beta-Protein Precursor genetics
Amyloid beta-Protein Precursor metabolism
Animals
Base Sequence
CHO Cells
Cricetinae
Cricetulus
Endocytosis
Humans
Low Density Lipoprotein Receptor-Related Protein-1 physiology
Protein Domains
Recombinant Proteins metabolism
Low Density Lipoprotein Receptor-Related Protein-1 genetics
Mutation, Missense
Point Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1559-1174
- Volume :
- 19
- Issue :
- 2-3
- Database :
- MEDLINE
- Journal :
- Neuromolecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 28612181
- Full Text :
- https://doi.org/10.1007/s12017-017-8446-x