# A Molecular Signaling Pathway Underlying Differential Predisposition of ApoE4 Genotype to Alzheimer's Disease

> **NIH NIH R00** · BROWN UNIVERSITY · 2021 · $232,097

## Abstract

PROJECT SUMMARY/ABSTRACT
Inheritance of Apolipoprotein E (ApoE) gene variant APOE-ϵ4 is the strongest genetic risk factor for
Alzheimer’s disease (AD), a rapidly growing burden of health care for the aging United States. There is a
fundamental gap in understanding how expression of APOE-ϵ4, which encodes ApoE isoform ApoE4,
influences neuronal function and contributes to AD pathogenesis. This gap, until filled, represents our
insufficiency in understanding AD and our inability to provide treatment and prevention to AD and risk carriers.
A central event in AD pathogenesis is deposition of amyloid-β (Aβ) peptide, generated from a series of
protease cleavages of amyloid precursor protein (APP). Using pure human neurons derived from human
embryonic stem cells or iPSCs, the applicant has recently identified a signaling pathway by which ApoE4
stimulates APP transcription and consequently induces Aβ production in neurons, more effectively than the
other two isoforms ApoE2 and ApoE3. This pathway hinges on double leucine-zipper kinase DLK and
downstream MAPK signaling, and is activated by three ApoE isoforms differentially in the potency rank order of
ApoE4>ApoE3>ApoE2, paralleling AD risk rank order. Given this striking ApoE isoform-specific effect, the
overall objective of this application is to determine whether and how ApoE4-specific activation of DLK/MAPK
signaling pathway may account for ApoE4’s deleterious AD-promoting effect. My central hypothesis is that
ApoE4 may predispose to AD by stimulating DLK/MAPK and increasing neuronal Aβ production chronically,
and that interference with ApoE-enhanced APP transcription via manipulations of DLK/MAPK pathway may
delay AD pathogenesis. I plan to test my central hypothesis, thereby accomplishing the overall objective for
this project by pursuing these following specific aims: 1) Determine whether DLK/MAPK pathway mediates
differential APP/Aβ induction by ApoE isoforms, ApoE4>ApoE3>ApoE2, 2) Identify the transcription control
elements of APP gene required for ApoE stimulation, and 3) Determine the functional output of DLK/MAPK
pathway in vivo. A combination of genetic and pharmacological manipulations will be used to enhance or inhibit
ApoE-activated DLK/MAPK pathway in cultured neurons and in animal brains. The molecular mechanism and
behavioral significance of this pathway will be rigorously examined. The overall approach is innovative
because it departs from the status quo by utilizing human neurons and focusing on the underappreciated
mechanisms of APP transcription in light of AD pathogenesis. The proposed research is significant, because it
is expected to define a new role of ApoE in the brain, and also to explore new therapeutic horizons by targeting
DLK-MAPK pathway as an alternative strategy. Findings will advance greatly our knowledge of AD
pathogenesis, and have strong potential for future translation into urgently needed treatment and prevention.

## Key facts

- **NIH application ID:** 10213580
- **Project number:** 5R00AG054616-05
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Yu-Wen Alvin Huang
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $232,097
- **Award type:** 5
- **Project period:** 2019-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213580

## Citation

> US National Institutes of Health, RePORTER application 10213580, A Molecular Signaling Pathway Underlying Differential Predisposition of ApoE4 Genotype to Alzheimer's Disease (5R00AG054616-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10213580. Licensed CC0.

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