APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1

Masaya Tachibana, Marie Louise Holm, Chia-Chen Liu, Mitsuru Shinohara, Tomonori Aikawa, Hiroshi Oue, Yu Yamazaki, Yuka A. Martens, Melissa E Murray, Patrick M. Sullivan, Kathrin Weyer, Simon Glerup, Dennis W Dickson, Guojun D Bu, Takahisa Kanekiyo

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Carrying the ε4 allele of the APOE gene encoding apolipoprotein E (APOE4) markedly increases the risk for late-onset Alzheimer’s disease (AD), in which APOE4 exacerbates the brain accumulation and subsequent deposition of amyloid-β (Aβ) peptides. While the LDL receptor–related protein 1 (LRP1) is a major apoE receptor in the brain, we found that its levels are associated with those of insoluble Aβ depending on APOE genotype status in postmortem AD brains. Thus, to determine the functional interaction of apoE4 and LRP1 in brain Aβ metabolism, we crossed neuronal LRP1-knockout mice with amyloid model APP/PS1 mice and APOE3–targeted replacement (APO3-TR) or APOE4-TR mice. Consistent with previous findings, mice expressing apoE4 had increased Aβ deposition and insoluble amounts of Aβ40 and Aβ42 in the hippocampus of APP/PS1 mice compared with those expressing apoE3. Intriguingly, such effects were reversed in the absence of neuronal LRP1. Neuronal LRP1 deficiency also increased detergent-soluble apoE4 levels, which may contribute to the inhibition of Aβ deposition. Together, our results suggest that apoE4 exacerbates Aβ pathology through a mechanism that depends on neuronal LRP1. A better understanding of apoE isoform–specific interaction with their metabolic receptor LRP1 on Aβ metabolism is crucial for defining APOE4-related risk for AD.

Original languageEnglish (US)
Pages (from-to)1272-1277
Number of pages6
JournalJournal of Clinical Investigation
Volume129
Issue number3
DOIs
StatePublished - Mar 1 2019

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LDL Receptors
Amyloid
Apolipoprotein E4
Pathology
Alzheimer Disease
Proteins
Brain
Apolipoproteins E
Apolipoprotein E3
Low Density Lipoprotein Receptor-Related Protein-1
Protein Deficiency
Knockout Mice
Detergents
oxidized low density lipoprotein
Hippocampus
Alleles
Genotype
Peptides
Genes

ASJC Scopus subject areas

  • Medicine(all)

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APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1. / Tachibana, Masaya; Holm, Marie Louise; Liu, Chia-Chen; Shinohara, Mitsuru; Aikawa, Tomonori; Oue, Hiroshi; Yamazaki, Yu; Martens, Yuka A.; Murray, Melissa E; Sullivan, Patrick M.; Weyer, Kathrin; Glerup, Simon; Dickson, Dennis W; Bu, Guojun D; Kanekiyo, Takahisa.

In: Journal of Clinical Investigation, Vol. 129, No. 3, 01.03.2019, p. 1272-1277.

Research output: Contribution to journalArticle

Tachibana, M, Holm, ML, Liu, C-C, Shinohara, M, Aikawa, T, Oue, H, Yamazaki, Y, Martens, YA, Murray, ME, Sullivan, PM, Weyer, K, Glerup, S, Dickson, DW, Bu, GD & Kanekiyo, T 2019, 'APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1', Journal of Clinical Investigation, vol. 129, no. 3, pp. 1272-1277. https://doi.org/10.1172/JCI124853
Tachibana, Masaya ; Holm, Marie Louise ; Liu, Chia-Chen ; Shinohara, Mitsuru ; Aikawa, Tomonori ; Oue, Hiroshi ; Yamazaki, Yu ; Martens, Yuka A. ; Murray, Melissa E ; Sullivan, Patrick M. ; Weyer, Kathrin ; Glerup, Simon ; Dickson, Dennis W ; Bu, Guojun D ; Kanekiyo, Takahisa. / APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 3. pp. 1272-1277.
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AU - Aikawa, Tomonori

AU - Oue, Hiroshi

AU - Yamazaki, Yu

AU - Martens, Yuka A.

AU - Murray, Melissa E

AU - Sullivan, Patrick M.

AU - Weyer, Kathrin

AU - Glerup, Simon

AU - Dickson, Dennis W

AU - Bu, Guojun D

AU - Kanekiyo, Takahisa

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