Neuschmid Stephan, Schallerer Carla, Ehrlich Barbara E, McGuone Declan
School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany.
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
Int J Mol Sci. 2025 Sep 22;26(18):9245. doi: 10.3390/ijms26189245.
Loss of calcium homeostasis, a shared feature of Alzheimer's Disease (AD) and Traumatic Brain Injury (TBI), activates enzyme-dependent cascades that promote protein misfolding, degrade synaptic architecture, impair axonal transport, and lead to neuronal death. Epidemiological studies identify TBI as a major risk factor for AD, yet the mechanistic basis for this association remains incompletely understood. Evidence from human and experimental studies implicate calcium dysregulation as a central link, triggering interconnected kinase, phosphatase, and protease networks that drive AD hallmark pathology, including amyloid-β (Aβ) accumulation and tau hyperphosphorylation. The calcium-dependent protease calpain is a key node in this network, regulating downstream enzyme activity, and cleaving essential scaffolding and signaling proteins. Selective vulnerability of the hippocampus and white matter to calcium-mediated damage may underlie cognitive deficits common to both conditions. In preclinical TBI and AD models, pharmacological inhibition of calcium-dependent enzymes confers neuroprotection. Recognizing disrupted calcium signaling as an upstream driver of post-traumatic neurodegeneration may enable early interventions to reduce AD risk among TBI survivors.
钙稳态失衡是阿尔茨海默病（AD）和创伤性脑损伤（TBI）的共同特征，它会激活依赖酶的级联反应，促进蛋白质错误折叠、破坏突触结构、损害轴突运输并导致神经元死亡。流行病学研究将TBI确定为AD的主要危险因素，但这种关联的机制基础仍未完全了解。来自人体和实验研究的证据表明，钙调节异常是一个核心环节，它触发相互关联的激酶、磷酸酶和蛋白酶网络，这些网络驱动AD标志性病理变化，包括淀粉样β蛋白（Aβ）积累和tau蛋白过度磷酸化。钙依赖性蛋白酶钙蛋白酶是这个网络中的关键节点，调节下游酶活性，并切割重要的支架蛋白和信号蛋白。海马体和白质对钙介导损伤的选择性易损性可能是这两种疾病共有的认知缺陷的基础。在临床前TBI和AD模型中，对钙依赖性酶的药理学抑制可提供神经保护作用。认识到钙信号紊乱是创伤后神经退行性变的上游驱动因素，可能有助于早期干预，以降低TBI幸存者患AD的风险。
