Virus and olfactory system interactions accelerate Alzheimer's disease pathology

点击翻译按钮获取中文摘要

PROJECT SUMMARY: Identification and treatment of risk factors that accelerate Alzheimer's disease (AD) are essential to slowing disease progression. Alphaherpesviruses (herpes simplex virus type 1 [HSV-1], varicella zoster virus [VZV]) are potential accelerators of AD because they increase dementia risk and produce similar pathologies, including amyloid, neuroinflammation, neurodegeneration, and cognitive impairment1-3. In parallel literature, early AD is characterized by smell loss4,5, amyloid deposition in olfactory epithelium (OE)6,7, and olfactory sensory neuron (OSN) dysfunction (reviewed in8). Because sniff-induced gamma () oscillations generated in olfactory bulb (OB) are directionally coupled to the hippocampus9-12, smell loss would result in decreased hippocampal  oscillations that have been postulated to lead to neurodegeneration and cognitive decline.14-16 Because alphaherpesviruses infect and reactivate in the nasal cavity, alphaherpesvirus disruption of olfactory pathways may accelerate AD. Our preliminary data show: (1) compared to controls, OB and olfactory tract (OT) from familial AD (FAD) subjects have upregulation of viral and inflammatory transcriptional pathways , confirmed at the protein level; (2) VZV immediate early protein 62 was detected in serum of 2 of 3 AD subjects and in 0/4 controls; (3) HSV-1- and VZV-infected human OE cultures (OECs) contain amyloid and increased OSN differentiation; and, (4) intranasal HSV-1-infected 5xFAD mice have increased OE amyloid and decreased olfaction compared to uninfected or pre-inoculation controls, respectively. Taken together, we hypothesize that alphaherpesvirus infection of the OE contributes to pathological processes within the olfactory system and hippocampus, thereby accelerating disease. To test this hypothesis, we will: (Aim 1) identify gene hippocampus, (Aim 2) determine whether infection of human OE with VZV and HSV-1 ex vivo elicits amyloid production and loss of odorant responsiveness, recapitulating smell loss in AD; and (Aim 3) test whether HSV- 1 worsens olfactory dysfunction in 5xFAD mice, accelerating the AD phenotype; specifically, we will test whether HSV-1-induced pathology and functional changes are diminished by optogenetic stimulation of mitral/tufted cells in the  frequency range and if entrainment of hippocampal  oscillations can prevent cellular and behavioral deficits elicited by HSV- 1. Understanding how viruses interact with the aging olfactory system, as well as with individuals who overexpress amyloidogenic peptides (FAD), to accelerate AD will identify potential biomarkers and therapies (e.g. vaccines or antiviral agents) that may slow or halt progression to clinical dementia, disability, and death. expression/pathways supportive of virus nfection in OE, OB, OT, entorhinal cortex, and biological fluids of FAD and sporadic AD (SAD) subjects; i