The molecular mechanism of Alzheimer’s disease (AD) pathogenesis remains obscure. Life and/or environmental events, such as traumatic brain injury (TBI), high-fat diet (HFD), and chronic cerebral hypoperfusion (CCH), are proposed exogenous risk factors for AD. BDNF/TrkB, an essential neurotrophic signaling for synaptic plasticity and neuronal survival, are reduced in the aged brain and in AD patients. Here, we show that environmental factors activate C/EBPβ, an inflammatory transcription factor, which subsequently up-regulates δ-secretase that simultaneously cleaves both APP and Tau, triggering AD neuropathological changes. These adverse effects are additively exacerbated in BDNF^+/− or TrkB^+/− mice. Strikingly, TBI provokes both senile plaque deposit and neurofibrillary tangles (NFT) formation in TrkB^+/− mice, associated with augmented neuroinflammation and extensive neuronal loss, leading to cognitive deficits. Depletion of C/EBPβ inhibits TBI-induced AD-like pathologies in these mice. Remarkably, amyloid aggregates and NFT are tempospatially distributed in TrkB^+/− mice brains after TBI, providing insight into their spreading in the progression of AD-like pathologies. Hence, our study revealed the roles of exogenous (TBI, HFD, and CCH) and endogenous (TrkB/BDNF) risk factors in the onset of AD-associated pathologies.

阿尔茨海默病 (AD) 发病机制的分子机制仍不清楚。生活和/或环境事件，例如创伤性脑损伤 (TBI)、高脂饮食 (HFD) 和慢性脑灌注不足 (CCH)，被认为是 AD 的外源性危险因素。BDNF/TrkB 是突触可塑性和神经元存活的重要神经营养信号，在老年大脑和 AD 患者中减少。在这里，我们显示环境因素激活 C/EBPβ，一种炎症转录因子，随后上调同时切割 APP 和 Tau 的 δ-分泌酶，引发 AD 神经病理学变化。这些不利影响在 BDNF ^+/-或 TrkB ^{+/-中进一步加剧}老鼠。^{引人注目的是，TBI 在 TrkB +/-}小鼠中引发老年斑沉积和神经原纤维缠结 (NFT) 形成，与增强的神经炎症和广泛的神经元丢失相关，从而导致认知缺陷。C/EBPβ 的消耗抑制了这些小鼠中 TBI 诱导的 AD 样病变。值得注意的是，淀粉样蛋白聚集体和 NFT 在 TBI 后 TrkB ^+/-小鼠大脑中的时空分布，提供了对它们在 AD 样病理进展中的传播的深入了解。因此，我们的研究揭示了外源性（TBI、HFD 和 CCH）和内源性（TrkB/BDNF）风险因素在 AD 相关病理发作中的作用。