# Role of LDLR in regulating metabolism of Apolipoprotein E and Amyloid-beta

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $393,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for Alzheimer’s disease (AD). Prevailing
evidence suggests that ApoE isoforms affect amyloid β (Aβ), tau, neuroinflammation, and synaptic plasticity. In
addition to isoforms, alteration in ApoE protein levels has been shown to influence neuroinflammation and Aβ
clearance. Previously, we reported the critical roles of ApoE receptor, low density lipoprotein receptor (LDLR),
in regulating ApoE clearance and Aβ levels in the brain. Overexpression of LDLR in the brain dramatically
inhibits amyloid formation by decreasing ApoE level and increasing Aβ clearance. These beneficial effects
were seen with as little as just 2-fold over-expression of LDLR. However, translating these observations into
therapy has been hampered by a poor understanding of cellular and molecular mechanism and a paucity of
effective approach to regulate the levels of LDLR in the brain. To overcome this critical barrier, we propose to
investigate cellular mechanism by which Inducible Degrader Of LDLR (IDOL) regulates LDLR, ApoE, Aβ, and
tau. In collaboration with Dr. Tontonoz (HHMI, UCLA), we found that global deletion of IDOL gene dramatically
increases LDLR levels and decreases apoE levels in the brain. IDOL is an E3 ubiquitin ligase that ubiquitinates
LDLR and targets it for degradation. Importantly, loss of IDOL expression significantly reduced amyloid plaque
burden and ameliorated neuroinflammation in an AD mouse model. Based on these strong preliminary data,
we now propose to determine the cellular and molecular mechanism by which IDOL affects ApoE and Aβ using
primary cells isolated from global and conditional knockout IDOL mouse model. We hypothesize that the
beneficial effect of IDOL deletion is mediated through LDLR-mediated ApoE level reduction and ApoER2-
mediated Reelin signaling. To test hour hypothesis, we will apply innovative methods, such as molecular
dynamics simulation, in vivo stable isotope pulse chase mass spectrometry, and in vivo Aβ and cytokines
microdialysis. Deciphering IDOL pathway in cellular details may help better understanding ApoE signaling in
basic biology and AD.

## Key facts

- **NIH application ID:** 9955130
- **Project number:** 5R01AG053242-05
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Jungsu Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2016-09-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955130

## Citation

> US National Institutes of Health, RePORTER application 9955130, Role of LDLR in regulating metabolism of Apolipoprotein E and Amyloid-beta (5R01AG053242-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9955130. Licensed CC0.

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