The role of STAT1 signal transduction in the pathogenesis of Alzheimer's disease

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Increasing evidence suggests that neuroinflammation contributes to the progression and severity of Alzheimer´s disease (AD), rather than being a mere bystander effect triggered by emerging amyloid-β plaques and neurofibrillar tangles. Histopathologically, activated microglia cluster around β-amyloid deposits, suggesting that phagocytosis by these cells is important for either the formation or clearance amyloid plaques. STAT (signal transducer and activator of transcription) proteins which function as key transcription factors in orchestrating immune reactions may play a crucial role in the pathophysiology of AD. In preliminary data from our two collaborating groups, we showed that chronic neuroinflammation associated with AD-related plaque deposition resulted in an increased expression of inflammatory cytokines, which in turn activated STAT1. Using a transgenic AD-like mouse model (5XFAD), we found that the absence of STAT1 expression resulted in a significantly reduced number of Iba1-positive microglial cells which was associated with a dramatically lower Aβ plaque load in various murine brain regions. Further experiments outlined in the project proposal will be required to assess the functional impact of different malfunctions in STAT1 signaling on the processing of β-amyloid precursor protein (APP), the regulation of plaque formation and the development of memory impairment. Studying the role of post-translation modifications and, in particular, sequence-specific, cooperative DNA binding of STAT1 at the molecular, cellular and organismic level, will provide further insight into the essential pathomechanisms leading to cognitive deficits in AD.