Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Neuroscience Program, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Mol Psychiatry. 2022 Aug;27(8):3396-3409. doi: 10.1038/s41380-022-01600-z. Epub 2022 May 11.
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/EBPβ/AEP signaling that drives AD pathologies and cognitive disorders. HFD stimulates diabetes and insulin resistance in neuronal Thy1-C/EBPβ transgenic (Tg) mice, accompanied with prominent mouse Aβ accumulation and hyperphosphorylated Tau aggregation in the brain, triggering cognitive deficits. These effects are profoundly diminished when AEP is deleted from C/EBPβ Tg mice. Chronic treatment with inflammatory lipopolysaccharide (LPS) facilitates AD pathologies and cognitive disorders in C/EBPβ Tg but not in wild-type mice, and these deleterious effects were substantially alleviated in C/EBPβ Tg/AEP -/- mice. Remarkably, the anti-inflammatory drug aspirin strongly attenuates HFD-induced diabetes and AD pathologies in neuronal C/EBPβ Tg mice. Therefore, our findings demonstrate that inflammation-activated neuronal C/EBPβ/AEP signaling couples diabetes to AD.
糖尿病是阿尔茨海默病（AD）的一个风险因素，AD 也被称为 3 型糖尿病，其患者大脑中存在胰岛素减少和胰岛素抵抗的现象。然而，将糖尿病与 AD 发病联系起来的分子机制仍不完全清楚。在这里，我们表明与肥胖相关的炎症以及高脂肪饮食（HFD）引起的糖尿病，会激活神经元 C/EBPβ/AEP 信号，从而导致 AD 病理和认知障碍。HFD 会刺激神经元 Thy1-C/EBPβ 转基因（Tg）小鼠发生糖尿病和胰岛素抵抗，伴随着大脑中明显的 Aβ 积累和过度磷酸化 Tau 聚集，从而引发认知缺陷。当从 C/EBPβ Tg 小鼠中删除 AEP 时，这些影响会大大减少。慢性给予炎症性脂多糖（LPS）会促进 C/EBPβ Tg 小鼠而不是野生型小鼠的 AD 病理和认知障碍，并且这些有害影响在 C/EBPβ Tg/AEP -/- 小鼠中得到了极大缓解。值得注意的是，抗炎药阿司匹林可显著减弱神经元 C/EBPβ Tg 小鼠中 HFD 诱导的糖尿病和 AD 病理。因此，我们的研究结果表明，炎症激活的神经元 C/EBPβ/AEP 信号将糖尿病与 AD 联系起来。
