Impact of atherosclerosis, metabolic syndrome, and STAT4-dependent immunity on Alzheimer's disease

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Project Summary The increasing evidence of cardiovascular disease-related Alzheimer’s disease (AD) progression, and the closely associated role of inflammation in both diseases, opens new opportunities for understanding AD mechanisms and has the potential to unveil novel avenues for therapeutic intervention. While data indicate that atherosclerosis promotes AD development, the role of atherosclerosis-associated immunity in AD is not fully understood. Our recent studies have revealed the role of Signal Transducer and Activator of Transcription 4 (STAT4) in critical neutrophil (N and macrophage (M functions in the context of Type 2 diabetes (T2D)- associated atherosclerosis. These findings, in conjunction with the increasing understanding of N and M roles in AD, suggest a novel pathway to study neuroinflammation in AD development. In this application, we propose to investigate how STAT4 shapes N M and neuronal functions, and thus affects neuroinflammation, long-term activity-dependent synaptic plasticity, cognitive and behavioral functions in conditions of T2D-accelerated atherosclerosis. Aim 1 will determine how STAT4 regulates immune-associated neuroinflammation and AD-like neuropathology in T2D-associated atherosclerosis. As we show that a high cholesterol/ high carb diet (DDC) feeding supports T2D development and atherosclerosis in Ldlr-/- mice, we will use this model as a model of T2D-associated atherosclerosis. Stat4-/- Ldlr-/- and Ldlr-/- mice will be fed DDC diet for 16 wks and neuroimmune cell composition, amyloid plaques deposition, microglia activation and blood-brain barrier breakdown will be examined. To test a role of STAT4 in neurons, irradiated 16 wk DDC fed Stat4fl/fl LysMcre/creLdlr-/- and Ldlr-/- mice transplanted with Ldlr-/- bone marrow will be analyzed for neuroimmune composition, Aβ deposition, neuronal apoptosis, and activation of microglia. Finally, we will test to what extent myeloid cell specific- and neuron-specific STAT4 regulates myeloid cell homing into the AD-like brain in series of adoptive transfer experiments. In Aim 2, we will examine the extent to which STAT4 regulates synaptic plasticity in T2D-accelerated atherosclerosis. Specifically, we will test the effect of STAT4 deficiency on basal synaptic transmission, presynaptic transmitter release, long-term potentiation and long-term depression of synaptic strength at Schaffer collateral-CA1 synapses, which play a critical role in learning and long-term memory consolidation, and are impaired in AD. We will also examine whether STAT4 deficiency alters behavioral and cognitive functions in Stat4-/-Ldlr-/- and Ldlr-/- mice. Overall, this proposal will forge new lines of investigation by identifying STAT4-dependent mechanisms by which STAT4 impacts neuroinflammation and potential AD risk under conditions of T2D-associated atherosclerosis.