Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Concise Communication Neuroscience Article has an altmetric score of 20

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

  • Text
  • PDF
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

×

Figure 2

ApoE4 exacerbates brain amyloid plaque burden depending on neuronal LRP1 in APP/PS1 mice.

Options: View larger image (or click on image) Download as PowerPoint
ApoE4 exacerbates brain amyloid plaque burden depending on neuronal LRP1...
(A–D) Brain Aβ was stained in APP/PS1; APOE3 control, APP/PS1; APOE3; nLrp1–/–, APP/PS1; APOE4 control, and APP/PS1; APOE4; nLrp1–/– mice with a pan-Aβ antibody at 9 months of age. Representative images of entire brain (A), hippocampus (B), cortical amyloid plaque (C), and CAA in leptomeningeal arteries (D) are shown. Scale bars: 1 mm (A); 200 μm (B); 20 μm (C and D). (E–H) Amyloid plaque burdens in the entire brain (E), cortex (F) and hippocampus (G) and CAA formation in leptomeningeal arteries (H) from the mice were quantified through the Positive Pixel Count program (Aperio Technologies) (n = 14–17/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, Tukey-Kramer post hoc analysis of 2-way ANOVA. White circles, data from female mice; black circles, data from male mice.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 1 news outlets
Posted by 7 X users
Referenced in 2 patents
On 3 Facebook pages
181 readers on Mendeley
See more details