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APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1
Masaya Tachibana, … , Guojun Bu, Takahisa Kanekiyo
Masaya Tachibana, … , Guojun Bu, Takahisa Kanekiyo
Published February 11, 2019
Citation Information: J Clin Invest. 2019;129(3):1272-1277. https://doi.org/10.1172/JCI124853.
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Concise Communication Neuroscience

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

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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.

Authors

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 Bu, Takahisa Kanekiyo

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Figure 3

ApoE4 increases insoluble Aβ levels in the hippocampus of APP/PS1 mice depending on neuronal LRP1.

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ApoE4 increases insoluble Aβ levels in the hippocampus of APP/PS1 mice d...
The concentrations of Aβ40 (A–C), Aβ42 (D–F), and apoE (G–I) in the hippocampus extracted in TBS, TBS-X, and GDN-HCl from APP/PS1; APOE3 control, APP/PS1; APOE3; nLrp1–/–, APP/PS1; APOE4 control, and APP/PS1; APOE4; nLrp1–/– mice were measured by ELISA at 9 months of age (n = 18–23/group). Horizontal lines, boxes, and whiskers correspond to median, IQR, and the furthest points within ×1.5 IQR from the box, respectively. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, Tukey-Kramer post hoc analysis of 2-way ANOVA. White circles, data from female mice; black circles, data from male mice.
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