High-fat diet-induced diabetes couples to Alzheimer's disease through inflammation-activated C/EBPbeta/AEP pathway

Abstract

<p>Diabetes is a risk factor for Alzheimer's disease (AD), which is also called type 3 diabetes with insulin reduction and insulin resistance in AD patient brains. However, the molecular mechanism coupling diabetes to AD onset remains incompletely understood. Here we show that inflammation, associated with obesity and diabetes elicited by high-fat diet (HFD), activates neuronal C/EBPbeta/AEP signaling that drives AD pathologies and cognitive disorders. HFD stimulates diabetes and insulin resistance in neuronal Thy1-C/EBPbeta transgenic (Tg) mice, accompanied with prominent mouse Abeta accumulation and hyperphosphorylated Tau aggregation in the brain, triggering cognitive deficits. These effects are profoundly diminished when AEP is deleted from C/EBPbeta Tg mice. Chronic treatment with inflammatory lipopolysaccharide (LPS) facilitates AD pathologies and cognitive disorders in C/EBPbeta Tg but not in wild-type mice, and these deleterious effects were substantially alleviated in C/EBPbeta Tg/AEP -/- mice. Remarkably, the anti-inflammatory drug aspirin strongly attenuates HFD-induced diabetes and AD pathologies in neuronal C/EBPbeta Tg mice. Therefore, our findings demonstrate that inflammation-activated neuronal C/EBPbeta/AEP signaling couples diabetes to AD.</p>