# Role of human apolipoprotein E isoforms in long-term effects of West Nile Virus exposure on Alzheimer's disease-related behavioral alteration, cognitive injury, neuroinflammation, and neuropathology

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $192,500

## Abstract

Project Summary
West Nile Virus (WNV) can cause severe and long-lasting neurological disease. Initial infection in the
hippocampus results in some of the neuropathology and neuroinflammation seen in Alzheimer's disease (AD).
There are three human apolipoprotein E (E) isoforms, which play a role in cholesterol metabolism: E2, E3, and
E4. Compared to E3, E2 is protective with regard to AD risk, while E4 is an AD risk factor. E4 is also associated
with enhanced entry of human immunodeficiency virus 1 (HIV-1) cell entry and HIV-1 disease progression. E
an
susceptibility
varicella
is
HIV-1-inducible inhibitor of viral production and infectivity in macrophages, involved i n the pathogenesis and
to other infectious diseases, including herpes simplex virus-1, hepatitis C virus, hepatitis E virus,
zoster virus, Epstein-Barr virus, malaria, (LM), andListeria monocytogenes Klebsiella pneumoniae. In
a mouse model of herpes simplex virus 1 (HSV-1), the cerebral load of latent HSV-1 genomic copies, which is
associated with the reactivation risk, is 10-fold higher in E4 than E3 mice. These apoE isoform differences might
involve very low-density lipoproteins (VLDL), as E4 binds better than E3 to VLDL and impairs their lipolytic
processing. WNV capsid protein binds VLDL, as does Dengue virus capsid protein and is thought to be important
for uptake and transport of virus. The differential interactions of apoE isoforms with human amyloid precursor
protein (APP) and with the amyloid peptides A40 and A42 generated from APP might influence cognitive injury
and neurodegeneration. APP, A40 and A42 might be important in viral infections as well and AD patients might
have an altered susceptibility to viral infections. We crossed APP NL-G-F mice with human apoE targeted
replacement (TR) mice and will use these mice for the proposed study. The hippocampus shows neuropathology
in brains of WNV patients and C57BL/6J wild-type mice infected with an attenuated WNV strain show spatial
learning impairments associated with interleukin 34 (IL-34)-dependent engulfment of presynaptic terminals by
activated microglia in the hippocampus during and after viral infection. We will determine whether prior exposure
to WNV worsens hAPP/A-induced behavioral alterations and cognitive impairments and neuropathology in 6-
and 12-month-old hAPP KI mice in an apoE isoform-dependent fashion, and whether these effects are
associated with enhanced neuroinflammation and microglial activation. We include novel wireless temperature
sensors to analyze body temperature and circadian rhythms following WNV exposure and as a function of
hAPP/A apoE isoform, and age. We will also assess cytokines and chemokines in plasma and brain.
Neuroinflammation, neuron loss and upregulation of APP and Aβ are not specific to AD and/or WNV infection.
While there is significant overlap between WNV and neurodegeneration pathogenesis, this has been understudied
and it is important to increase our understanding about th...

## Key facts

- **NIH application ID:** 10848463
- **Project number:** 5R21AG079158-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** ALEC J HIRSCH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2023-05-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848463

## Citation

> US National Institutes of Health, RePORTER application 10848463, Role of human apolipoprotein E isoforms in long-term effects of West Nile Virus exposure on Alzheimer's disease-related behavioral alteration, cognitive injury, neuroinflammation, and neuropathology (5R21AG079158-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848463. Licensed CC0.

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