# Effect of APOE on CNS Neurons: Role of LRP

> **NIH NIH RF1** · WASHINGTON UNIVERSITY · 2020 · $3,652,704

## Abstract

APOE genotype is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). A complete
understanding of its role in AD pathogenesis remains unclear. In addition to the effects of apoE on Aβ
clearance and aggregation, it is also likely to also influence AD via other mechanisms. Over the last 4.5 years
of this grant, we have utilized a mouse model that develops tauopathy and neurodegeneration (P301S Tau Tg
mice) and found that all human isoforms of apoE significantly enhance tau-mediated brain volume/neuronal
loss and disease associated microglial and astrocyte response with apoE4 having the strongest effects.
Interestingly, tau-mediated neurodegeneration and the enhanced innate immune response was strongly
attenuated in the absence of apoE. Using a cell culture model, we also found that glial-derived apoE,
particularly apoE4, could exacerbate neuronal damage, an effect that appears to involve apoE’s ability to
enhance inflammation. In preliminary data, we have now found that if we overexpress the low density
lipoprotein receptor (LDLR) in the brain of P301S Tau Tg mice, we can markedly lower apoE and attenuate
brain atrophy, decrease p-tau levels, and decrease the disease associated microglial-response. We also found
that cultured astrocytes secrete apoE in cholesterol/phospholipid rich HDL-like particles whereas cultured
microglia secrete apoE in small, poorly lipidated particles. While these findings suggest important roles for
apoE in modulating tau-mediated neurodegeneration, there are a number of important unanswered questions
to address to better understand these effects. They include 1) Are astrocytes or microglia the main source of
apoE that mediates these effects? 2) In addition to effects on Aβ, does astrocyte vs. microglial apoE in an
isoform-specific fashion affect Aβ-induced tau seeding and spreading? 3) How do astrocyte and microglial-
derived apoE particles differ, what is their structure and how does it differ by isoform, and do these differences
result in different biological effects? 4) How and what is the source of apoE that influences the brain’s innate
immune response to influence tau-mediated neurodegeneration? These questions lead us to hypothesize
that apoE, particularly apoE4, influences the brain’s innate immune response to exacerbate tau-
mediated neurodegeneration and Aβ-induced tau seeding/spreading. We propose these Aims: Aim 1: To
determine whether apoE produced by astrocytes or microglia influences tau-mediated neurodegeneration
using newly generated conditional apoE KI mice. Aim 2: To determine whether apoE produced by astrocytes
or microglia influences human AD tau seeding/spreading +/- Aβ as well as CSF and plasma levels of p-tau,
tau, Aβ, and apoE using a well characterized mouse model that develops Aβ amyloidosis APPNL-F KI mice. Aim
3: To characterize apoE particles produced by astrocytes and microglia both in vitro and in vivo via lipidomics
and cryoEM. We will utilize a variety of techniques ...

## Key facts

- **NIH application ID:** 9881454
- **Project number:** 2RF1NS090934-24
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** DAVID M. HOLTZMAN
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,652,704
- **Award type:** 2
- **Project period:** 1996-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881454

## Citation

> US National Institutes of Health, RePORTER application 9881454, Effect of APOE on CNS Neurons: Role of LRP (2RF1NS090934-24). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/9881454. Licensed CC0.

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