# ApoE4 and C/EBP: Mutually Regulate Each Other in Alzheimer's Disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $464,866

## Abstract

ApoE4 is the major genetic risk factor for Alzheimer's disease (AD) pathogenesis. In the central nervous
system (CNS), ApoE is mainly produced by glia and astrocytes and transports cholesterol to neurons via ApoE
receptors, which are members of the low density lipoprotein receptor (LDLR) gene family. ApoE isoform-
specific interactions with Aβ, namely ApoE/Aβ complex, modulates Aβ levels and is implicated in Aβ
clearance. C/EBPβ is an inflammatory cytokines-regulated transcription factor that can be activated by Aβ as
well. Interestingly, we have recently reported that C/EBPβ acts as an age-dependent transcription factor for
delta-secretase (AEP, also called legumain). This crucial protease cleaves both APP and Tau in human AD
brains and AD mouse models, promoting amyloidogenic pathway and neurofibrillary tangle (NFT) formation.
Inactivation of delta-secretase substantially decreases Aβ deposits and NFT aggregation and abolishes AD
pathologies in various AD mouse models. In our preliminary studies, we found that C/EBPβ binds ApoE
promoter and dictates ApoE mRNA transcription during aging. Knockout of C/EBPβ in 3xTg greatly reduces
ApoE levels and senile plaques. On the other hand, ApoE4 but not E3 strongly activates C/EBPβ in primary
neurons. Blockage of ApoE4 interaction with its receptor diminishes this effect. Moreover, 27-
hydroxycholesterol displays much stronger effect in stimulating C/EBPβ than cholesterol in the presence of
ApoE4. Hence, we hypothesize that ApoE4 and 27-oxycholesterol trigger C/EBPβ activation, which feeds
back and upregulates ApoE transcription in AD pathogenesis. Consequently, this vicious loop may
facilitate AD pathologies via escalating delta-secretase levels. To define the molecular mechanisms between
ApoE4/C/EBPβ crosstalk will provide an innovative insight into the pathological roles of ApoE4 in AD onset
and progression.

## Key facts

- **NIH application ID:** 10816974
- **Project number:** 5R01AG065177-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** GUY Martin BENIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $464,866
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816974

## Citation

> US National Institutes of Health, RePORTER application 10816974, ApoE4 and C/EBP: Mutually Regulate Each Other in Alzheimer's Disease (5R01AG065177-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10816974. Licensed CC0.

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