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Principal Investigator: MICHAEL G ROSENFELD
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $399,310
Funding agency: National Institute on Aging
ABSTRACT
Alzheimer’s disease (AD) presents a formidable therapeutic challenge, as current interventions have failed
to slow disease progression. The majority of AD genetic risk variants identified by GWAS reside in non-
coding regions of the genome, suggesting that alterations in gene expression contribute to susceptibility for
sporadic AD. Multiple reports now suggest that Herpes Simplex Virus 1 (HSV1) and other microbes can
accumulate in the brain to increase the incidence of AD/dementia. While there is evidence linking reactivation
of latent HSV1 infection to AD, the pathological potential of the latent state per se has not been addressed.
Furthermore, there is now concern that COVID-19, which is caused by the pandemic SARS-CoV-2 and can
include neurological and neurocognitive sequelae, might impact the onset or course of AD. Here we propose to
advance recent findings by employing powerful new genomic technologies to characterize the cell type-specific
transcriptional impact and cell autonomous vs non-cell autonomous effects of specific viral gene products,
including HSV1 latency lncRNA transcripts and the SARS-CoV-2 Spike protein, that contribute to neurotoxic
programs characteristic of sporadic AD. Using a modified single-nucleus sequencing approach, which allows
for DNA accessibility and global transcription to be assessed simultaneously in the same nucleus, we will
continue our interrogation of human control and AD brain samples to reveal cell type-specific aging vs
pathological trajectory trees for each CNS cell type in sporadic AD, ultimately allowing for the identification of the
key transcription factors acting at implicated regulatory enhancers. This will enable us to elucidate how viral
gene products alter enhancer landscapes and transcriptional networks related to sporadic AD in various neuronal
and non-neuronal cell types and subtypes. In addition, we will investigate the hypothesis that the sense (S) and
antisense (AS) LATs impact transcription by associating with specific regulatory elements in the host genome in
collaboration with the co-regulator KAP1 to impact expression of multiple AD susceptibility loci. We further
hypothesize that the S-LAT influences the AD process by causing neuronal dysfunction and inflammatory glial
activation, at least in part, through down-regulation of gene clusters encoding KRAB zinc-finger proteins (KZFPs)
that normally repress human endogenous retrovirus (HERV) repeats, whereas the AS-LAT tempers these
deleterious effects by promoting an anti-inflammatory gene expression profile and can further mitigate the innate
immune response as well as cell death programs through direct inhibition of the AD-associated, sentinel kinase
PKR in a non-genomic fashion. Collectively, the proposed studies will yield crucial cell type-specific insights into
pathological trajectories in sporadic AD that may be subject to modulation by diverse infectious as well as non-
microbial insults to the brain.
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