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，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 患者中会减少。在这里，我们发现环境因素激活 C/EBPβ（一种炎症转录因子），随后上调 δ-分泌酶，同时裂解 APP 和 Tau，引发 AD 神经病理变化。这些副作用在 BDNF ^+/-或 TrkB ^+/-小鼠中进一步加剧。引人注目的是，TBI 会在 TrkB ^+/-小鼠中引起老年斑沉积和神经原纤维缠结 (NFT) 形成，与神经炎症加剧和广泛神经元损失相关，导致认知缺陷。 C/EBPβ 的消耗可抑制 TBI 诱导的这些小鼠的 AD 样病理。值得注意的是，淀粉样蛋白聚集体和 NFT 在 TBI 后 TrkB ^+/-小鼠大脑中呈时空分布，这为了解它们在 AD 样病理进展中的扩散提供了深入的了解。因此，我们的研究揭示了外源性（TBI、HFD 和 CCH）和内源性（TrkB/BDNF）危险因素在 AD 相关病理发生中的作用。