This Project Summary/Abstract was originally submitted with R01 AG073193 and is included here unchanged
to satisfy submission system requirements.
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
