APP‐C31: An Intracellular Promoter of Both Metal‐Free and Metal‐Bound Amyloid‐β40 Aggregation and Toxicity in Alzheimer's Disease

Author:

Nam Eunju1ORCID,Lin Yuxi2,Park Jiyong13,Do Hyunsu4,Han Jiyeon1,Jeong Bohyeon5,Park Subin56,Lee Da Yong5,Kim Mingeun1,Han Jinju4ORCID,Baik Mu‐Hyun13ORCID,Lee Young‐Ho278910,Lim Mi Hee1ORCID

Affiliation:

1. Department of Chemistry Korea Advanced Institute of Science and Technology (KAIST) Daejeon 34141 Republic of Korea

2. Research Center for Bioconvergence Analysis Korea Basic Science Institute (KBSI) Ochang Chungbuk 28119 Republic of Korea

3. Center for Catalytic Hydrocarbon Functionalizations Institute for Basic Science (IBS) Daejeon 34141 Republic of Korea

4. Graduate School of Medical Science and Engineering KAIST Daejeon 34141 Republic of Korea

5. Rare Disease Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon 34141 Republic of Korea

6. Department of Biochemistry Department of Medical Science Chungnam National University School of Medicine Daejeon 35015 Republic of Korea

7. Bio‐Analytical Science University of Science and Technology (UST) Daejeon 34113 Republic of Korea

8. Graduate School of Analytical Science and Technology Chungnam National University Daejeon 34134 Republic of Korea

9. Department of Systems Biotechnology Chung‐Ang University Gyeonggi 17546 Republic of Korea

10. Frontier Research Institute for Interdisciplinary Sciences Tohoku University Miyagi 980‐8578 Japan

Abstract

AbstractIntracellular C‐terminal cleavage of the amyloid precursor protein (APP) is elevated in the brains of Alzheimer's disease (AD) patients and produces a peptide labeled APP‐C31 that is suspected to be involved in the pathology of AD. But details about the role of APP‐C31 in the development of the disease are not known. Here, this work reports that APP‐C31 directly interacts with the N‐terminal and self‐recognition regions of amyloid‐β40 (Aβ40) to form transient adducts, which facilitates the aggregation of both metal‐free and metal‐bound Aβ40 peptides and aggravates their toxicity. Specifically, APP‐C31 increases the perinuclear and intranuclear generation of large Aβ40 deposits and, consequently, damages the nucleus leading to apoptosis. The Aβ40‐induced degeneration of neurites and inflammation are also intensified by APP‐C31 in human neurons and murine brains. This study demonstrates a new function of APP‐C31 as an intracellular promoter of Aβ40 amyloidogenesis in both metal‐free and metal‐present environments, and may offer an interesting alternative target for developing treatments for AD that have not been considered thus far.

Funder

National Research Foundation of Korea

National Research Council of Science and Technology

Korea Basic Science Institute

Institute for Basic Science

Ministry of Education

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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