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

点击翻译按钮获取中文摘要

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).