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Clusterin Binding Modulates the Aggregation and Neurotoxicity of Amyloid-β(1–42)

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) aggregates in the brain. Clusterin (CLU), also known as apolipoprotein J, is a potent risk factor associated with AD pathogenesis, in which Aβ aggregation is essentially involved. We observed close colocalization of CLU and Aβ(1–42) (Aβ42) in parenchymal amyloid plaques or vascular amyloid deposits in the brains of human amyloid precursor protein (hAPP)-transgenic Tg2576 mice. Therefore, to elucidate the binding interaction between CLU and Aβ42 and its impact on amyloid aggregation and toxicity, the two synthetic proteins were incubated together under physiological conditions, and their structural and morphological variations were investigated using biochemical, biophysical, and microscopic analyses. Synthetic CLU spontaneously bound to different possible variants of Aβ42 aggregates with very high affinity (Kd = 2.647 nM) in vitro to form solid CLU–Aβ42 complexes. This CLU binding prevented further aggregation of Aβ42 into larger oligomers or fibrils, enriching the population of smaller Aβ42 oligomers and protofibrils and monomers. CLU either alleviated or augmented Aβ42-induced cytotoxicity and apoptosis in the neuroblastoma-derived SH-SY5Y and N2a cells, depending on the incubation period and the molar ratio of CLU:Aβ42 involved in the reaction before addition to the cells. Thus, the effects of CLU on Aβ42-induced cytotoxicity were likely determined by the extent to which it bound and sequestered toxic Aβ42 oligomers or protofibrils. These findings suggest that CLU could influence amyloid neurotoxicity and pathogenesis by modulating Aβ aggregation.

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Data Availability

The data obtained during the present study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

Abbreviations

Aβ:

Amyloid-β

Aβ42:

Aβ(1–42)

AD:

Alzheimer’s disease

ADDL:

Aβ-derived diffusible ligand

Alexa633:

Alexa Fluor 633

Alexa633–CLU:

Alexa633-labeled CLU

CLSM:

Confocal laser scanning microscopy

CLU:

Clusterin

co-IP:

Co-immunoprecipitation

ELISA:

Enzyme-linked immunosorbent assay

FCCS:

Fluorescence cross-correlation spectroscopy

FCS:

Fluorescence correlation spectroscopy

FITC:

Fluorescein isothiocyanate

FITC–Aβ42:

FITC-conjugated Aβ42

hAPP:

Human amyloid precursor protein

HRP:

Horseradish peroxide

LSM:

Laser scanning microscope

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PAGE:

Polyacrylamide gel electrophoresis

PBS:

Phosphate-buffered saline

PI:

Propidium iodide

PPI:

Protein–protein interaction

TEM:

Transmission electron microscopy

WT mice:

Wild-type mice

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Acknowledgements

We thank the Confocal Microscope and Electron Microscopy core facility at the ConveRgence mEDIcine research cenTer (CREDIT; Asan Medical Center) for their support and instrumentation.

Funding

This study was supported by the National Research Foundation, Ministry of Science & ICT (MSIT), Republic of Korea (NRF-2015R1A2A1A15052049 and NRF-2020R1F1A1048577 to JYL, and NRF-2018R1D1A1B07048696 to CGP), and the Asan Institute for Life Sciences, Asan Medical Center (2019IP0857 to JYL).

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Authors and Affiliations

  1. Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Yun-Mi Kim & Su Yeon Choi

  2. Asan Institute for Life Sciences, Asan Medical Center, Seoul, 05505, Republic of Korea

    Yun-Mi Kim, SuJi Park, Su Yeon Choi, Shin Bi Oh, MinKyo Jung, Chan-Gi Pack, Jung ** Hwang, Eunyoung Tak & Joo-Yong Lee

  3. Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Chan-Gi Pack, Eunyoung Tak & Joo-Yong Lee

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All authors contributed to the study conception and design, experimental performance, and data analysis and interpretation. The first draft of the manuscript was cooperatively prepared by the first five co-authors (Yun-Mi Kim, Su Yeon Choi, SuJi Park, Shin Bi Oh, and MinKyo Jung), and the last four co-authors (Chan-Gi Pack, Jung ** Hwang, Eunyoung Tak, and Joo-Yong Lee) commented on and wrote the final version of the manuscript. All authors read and approved the final manuscript and this publication.

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Correspondence to Joo-Yong Lee.

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Kim, YM., Park, S., Choi, S.Y. et al. Clusterin Binding Modulates the Aggregation and Neurotoxicity of Amyloid-β(1–42). Mol Neurobiol 59, 6228–6244 (2022). https://doi.org/10.1007/s12035-022-02973-6

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