ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1600119
Effects of West Nile Virus on behavioral and cognitive performance, cortical Ab pathology, viral loads, and immune measures of middle-aged NL-G-F/E3 and NL-G-F/E4 mice
Provisionally accepted
Jacob Raber1*
Abigail O'Niel2
Christopher J Parkins2Alexandra Pederson2Elizabeth Saltonstall2Emily Bunnell2Ria Aggarwal2Phoebe Sandholm2Kat Kessler2Henry F Harrison2Jessica L Smith2Alec J Hirsch2- 1Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, United States
- 2Oregon Health and Science University, Portland, Oregon, United States
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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 ADsusceptibility genes (i.e., E4) and by inducing neuroinflammation (i.e., increases in TCR-a, IFN-g, TNF-a, 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 knockin (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/Ab-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.
Keywords: West Nile virus, Apolipoprotein E, amyloid precursor protein, Behavioral testing, Cognitive testing, Body Temperature, Amyloid pathology, Viral Load
Received: 26 Mar 2025; Accepted: 27 May 2025.
Copyright: © 2025 Raber, O'Niel, Parkins, Pederson, Saltonstall, Bunnell, Aggarwal, Sandholm, Kessler, Harrison, Smith and Hirsch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jacob Raber, Behavioral Neuroscience, Oregon Health and Science University, Portland, 97239, Oregon, United States
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