# Targeting IDOL-ApoE receptor pathway in Alzheimer's disease

> **NIH NIH R56** · OHIO STATE UNIVERSITY · 2021 · $393,750

## Abstract

Apolipoprotein E (APOE) genotype has long been known to strongly influence the risk and
the onset of Alzheimer’s disease(AD), yet the exact mechanisms underlying remain
incompletely defined. Accumulating evidence suggested that the functional combination of ApoE
and its receptors act together to modify the risk for AD, and targeting brain ApoE receptors has
recently emerged as a promising therapeutic strategy to combat AD. However, the lack of
knowledge on the endogenous pathways regulating brain ApoE receptors is a major hurdle to
advance ApoE receptors as accessible therapeutic targets in AD.
 Previously, we have identified the inducible degrader of the LDLR (IDOL), an E3 ubiquitin
ligase, is a major post-translational regulator of three brain ApoE receptors: low-density
lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), and ApoE Receptor
2 (ApoER2). Each of these three ApoE receptor plays key role in modulating ApoE actions and
impacting AD pathogenesis. Our studies showed the genetic deletion or pharmacological
inhibition of IDOL in the brain significantly increase the protein levels of ApoE receptors,
ameliorate amyloid-β (Aβ) pathology, and improve cognitive functions in an AD mouse model,
suggesting inhibition of brain IDOL activity may serve as a promising therapeutic strategy for
AD. For the mechanistic and therapeutic implications, we propose to further investigate the
multifactorial role and molecular mechanisms of IDOL-ApoE receptors pathway in modulating
ApoE actions and impacting AD pathology. Aim 1 is to characterize the microglia-intrinsic role of
IDOL in Aβ pathology. Aim 2 is to elucidate the mechanisms on how IDOL reduction facilitates
microglia response to Aβ pathology. Aim 3 is to define the role of neuronal IDOL-ApoER2
pathway in protecting against ApoE4-induced synaptic dysfunction and cognitive deficit in AD.

## Key facts

- **NIH application ID:** 10461318
- **Project number:** 1R56AG073310-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jie Gao
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,750
- **Award type:** 1
- **Project period:** 2021-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461318

## Citation

> US National Institutes of Health, RePORTER application 10461318, Targeting IDOL-ApoE receptor pathway in Alzheimer's disease (1R56AG073310-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10461318. Licensed CC0.

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