Antiviral response coupled with transposon derepression in Alzheimer's disease and aging

Project Summary/Abstract
Alzheimer's disease (AD) significantly impacts aging populations worldwide. Inflammation, at cell and organismic
levels, often accompanies aging process; whereas in sporadic AD, neuroinflammation is increasingly recognized
as a major contributor. However, the molecular triggers for neuroinflammatory response and factors mediating
and regulating the process remains enigmatic. Antiviral defense mechanisms control nucleic acid-based
parasites, most noticeably the invading viruses. Type I IFN (IFN) cytokines, a key component of antiviral innate
immunity, is a product of signaling activation of mammalian nucleic acid innate immune sensors that detect viral
genomes or their replication products. We recently reported that plaque-associated microglia innately reacted to
nucleic acid-containing amyloid β (Aβ) plaques and promote chronic gliosis and synapse loss in various Aβ
models. While grossly upregulated in clinic AD, IFN pathway unexpectedly escalates with increased BRAAK
staging, which implies an idiosyncratic IFN response in association with human tau pathology. We have since
confirmed a prominent IFN pathway activation in different murine tauopathy models. Genomic instability is a core
hallmark of aging. Senescent cells dysregulate their epigenome and derepress transposable elements (TE or
transposons), endogenous parasites widely distributed in the genome. Consequently, activation of L1
retrotransposable element triggers an antiviral innate immune response, resulting in IFN production. In parallel,
we found that tau overexpression relaxed neuronal heterochromatin, which is correlated with elevated
transcription of L1 and other TEs in tauopathy brains. Remarkably, IFN signaling is activated in aging brain and
polymorphisms of several ISGs as a group impose as a risk factor for AD. Based on these intriguing findings,
we seek to investigate how antiviral immune response is coupled to derepressed transposon activity during AD
pathogenesis in this proposal. Specifically, we plan to examine the involvement of L1 and retroelements in
conjunction with the onset of neuroinflammation under tauopathy and aging conditions (aim 1), identify the key
signaling mediators facilitating tau-stimulated antiviral response in the brain (aim 2) and elucidate epigenetic
influence on transposon derepression and antiviral inflammation in tauopathy and brain aging (aim 3).

Grant Number: 5R01AG074283-05
NIH Institute/Center: NIH
Principal Investigator: Wei Cao