Selective vulnerability of the locus coeruleus and hypothalamus to HSV-1 infection in Alzheimer's disease progression

. Alzheimer's disease (AD) is characterized not only by progressive memory loss but also by a range of non- cognitive deficits, including sleep disturbances and autonomic dysfunction. Emerging evidence implicates herpes simplex virus type 1 (HSV-1) as a critical environmental trigger that accelerates AD pathology. Our preliminary data demonstrates that HSV-1 preferentially infects the locus coeruleus (LC) and paraventricular nucleus of the hypothalamus (PVN) in both wild-type (WT) and AD mouse model mice—key regulators of non- cognitive functions—to induce early amyloid deposition, tau hyperphosphorylation, and neuroinflammatory responses, ultimately exacerbating AD progression. Furthermore, HSV-1 exacerbates microglia dysfunction and amyloid accumulation in AD mice. These observations raise a critical question: does HSV-1 infection initiate early transcriptional and post-translational changes in the LC and PVN that accelerate physiological and behavioral deficits? In this proposal, we hypothesize that HSV-1 induces Aβ and NFT formation in the LC and PVN, triggering a hyperinflammatory response prior to hippocampal involvement. To test this hypothesis, we will employ an integrated, multidisciplinary approach using advanced spatial transcriptomics and proteomics (via the NanoString GeoMx DSP platform) alongside in vivo electrophysiological (EEG/LFP) and behavioral assays (using FED3 feeding devices). Aim 1 will delineate the spatial and temporal molecular alterations in the LC and PVN following intranasal HSV-1 infection in 3xTg AD mouse models and WT controls. This analysis will focus on the regional accumulation of amyloid and tau pathologies, microglial activation, and associated gene expression changes that precede hippocampal involvement. In Aim 2, we will link these molecular changes to functional outcomes by monitoring disruptions in LC activity, sleep-wake cycles, EEG rhythms, and feeding behavior. This study is innovative in its use of state-of-the-art spatial omics combined with rigorous neurophysiological and behavioral assessments to bridge the gap between molecular pathology and functional deficits in AD. The outcomes are expected to provide critical insights into HSV-1's role in triggering early AD pathogenesis, particularly in non-cognitive domains, and may identify novel targets for early intervention. Ultimately, this research will help reshape our understanding of viral contributions to neurodegenerative processes and inform the development of therapeutic strategies aimed at mitigating both cognitive and non-cognitive symptoms of AD. Project Number: 1R21AG093719-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Christy Niemeyer | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $442,485 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 AN-Z (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301407