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

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 the similarities as this will facilitate the identification of novel biomarkers and therapeutic strategies for AD and other neurodegenerative disorders. This proposal is submitted in response to PAR-22-094 and NOT-AG-21-039.