# Targeting the apoE/A-beta Interaction as a Therapeutic Approach for AD

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $419,783

## Abstract

Alleles of the apolipoprotein (apo) E gene are by far the strongest identified genetic risk factor modulating
susceptibility to sporadic Alzheimer's disease (AD) and the burden of β-amyloid (Aβ) deposition in the brain
following the rank order of ε4>>ε3>ε2. Encoded by these alleles, apoE isoforms differ structurally and
functionally but all bind in vitro synthetic Aβ peptide promoting its ε-sheet folding and fibrillar assembly.
Knockout (KO) of the Apoe gene in APP transgenic (Tg) mice prevents formation of fibrillar Aβ plaques and
vascular deposits, confirming a critical role for apoE as a catalyst of Aβ deposition in vivo. In the current period
of this award we developed APPSW/PS1dE9/apoE-TR mice (APP/E-TR) with targeted replacement (TR) of the
mouse Apoe gene with various human APOE alleles, which faithfully reproduce the differential effect of apoE
isoforms on the magnitude of Aβ deposition. We showed that systemic treatment of APP/E2 and APP/E4 mice
with Aβ12-28P, which is a brain permeable synthetic peptide that binds apoE and prevents apoE/Aβ
interaction, lowers Aβ deposition and level of toxic Aβ oligomers and attenuates neuritic degeneration in both
lines of mice. This observation suggests a notion that targeting the apoE/Aβ interaction could reduce Aβ
deposition in carriers of all types of APOE alleles. Development of apoE/Aβ antagonists for possible clinical
application remains however problematic since neither the Aβ binding domain on apoE nor the structure of Aβ
“super epitope” within its 12-28 sequence responsible for apoE interaction are presently known. In addition to
catalyzing deposition of fibrillar Aβ, apoE isoforms also show differential effect on the clearance of soluble Aβ
from the brain interstitial space, modulate microglia response and synaptic plasticity. Modus operandi of apoE
on the clearance of Aβ from the interstitial fluid (ISF) remains elusive. Our preliminary microdialysis work
indicates substantial interaction between apoE and soluble Aβ in the brain ISF, and suggests that apoE/Aβ
antagonists may enhance soluble Aβ clearance and prevent Aβ oligomerization. This indicates potential for
targeting the apoE/Aβ interaction as a disease preventive measure. In addition, systemic treatment of APP and
APP/E-TR mice with Aβ12-28P reduces amyloid angiopathy and perivascular microhemorrhages and
attenuates microglia activation, which suggests that combining an apoE/Aβ antagonist with anti-Aβ passive
immunization could temper chronic inflammation and vasculotropic complications produced by the latter, while
having synergistic outcome on Aβ reduction. The specific aims are: 1) To identify the Aβ binding domain on
apoE and characterize its variability across apoE isoforms and to determine the structure of Aβ super epitope
for apoE interaction. 2) To investigate how apoE isoforms differentially modulate soluble Aβ metabolism in the
ISF and to study how targeting apoE/Aβ interaction improves Aβ clearance and attenuates its oligo...

## Key facts

- **NIH application ID:** 9930007
- **Project number:** 5R01AG031221-10
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** MARTIN Joseph SADOWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,783
- **Award type:** 5
- **Project period:** 2008-03-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930007

## Citation

> US National Institutes of Health, RePORTER application 9930007, Targeting the apoE/A-beta Interaction as a Therapeutic Approach for AD (5R01AG031221-10). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/9930007. Licensed CC0.

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