# Effects of West Nile virus on behavioral and cognitive performance, cortical Aβ pathology, viral loads, and immune measures of middle-aged NL-G-F/E3 and NL-G-F/E4 mice

## TL;DR

This study shows that West Nile virus affects mice differently based on their genetic makeup, especially impacting cognitive function and viral load in those with a specific Alzheimer's risk gene.

## Contribution

The study reveals a novel apoE isoform-dependent effect of West Nile virus on cognitive injury and viral persistence in a mouse model of Alzheimer's disease.

## Key findings

- KUNV exposure impacts physiological and cognitive measures in NL-G-F mice depending on their apoE isoform.
- NL-G-F/E4 mice showed greater susceptibility to cognitive injury and prolonged viral load in the cortex.
- ApoE isoforms modulate immune and amyloid pathology following WNV exposure in the NL-G-F AD mouse model.

## Abstract

West Nile Virus (WNV) can cause severe and long-lasting neurological disease and results in some neuropathology and neuroinflammation seen in Alzheimer’s disease (AD). Exposure to WNV might impact AD-relevant behavioral and cognitive performance and neuropathology via AD-susceptibility genes (i.e., E4) and by inducing neuroinflammation (i.e., increases in TCR-α, IFN-γ, TNF-α, and CXCL- 10). There are three human apolipoprotein E (E) isoforms, which play a role in cholesterol metabolism: E2, E3, and E4. Compared to E3, E4 is an AD risk factor.

We crossed knock-in (KI) mice expressing human amyloid precursor protein (APP) containing the dominant NL-G-F mutations with human apoE targeted replacement (TR) mice and used middle-aged NL-G-F/E3 and NL-G-F/E4 mice to assess the role of prior WNV (subtype Kunjin virus) (KUNV) exposure on hAPP/Aβ-induced behavioral alterations, cognitive injury, circadian body temperatures, viral loads, neuropathology, and transcript levels of four immune measures important in the detrimental effects of KUNV on brain function.

KUNV affected physiological, behavioral, cognitive, amyloid pathology, viral load, and immune measures in middle aged NL-G-F mice in an apoE isoform-dependent fashion. NL-G-F/E4 mice were more susceptible to KUNV induced cognitive injury and prolonged viral load in the cortex.

These results support an important apoE isoform-dependent role in modulating phenotypes in the NL-G-F AD mouse model following WNV exposure.