Tang Luhong, Liu Feng, Sun Xuefei, Yang Jiaoyan, Liu Yifang, Pan Xueting, Hao Liying, Lou Fan, Su Jingyang
Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China.
Department of Endocrinology and Metabolism, The Fourth People's Hospital of Shenyang, China Medical University, Shenyang, 110000, China.
Arch Toxicol. 2025 Sep 1. doi: 10.1007/s00204-025-04160-7.
Alzheimer's disease (AD), a neurodegenerative "memory killer" demanding urgent global intervention, has long been shrouded in mystery regarding its core pathological mechanisms. Although the traditional amyloid-β (Aβ) hypothesis remains dominant, recent groundbreaking research has revealed that early activation of aberrant calcium (Ca⁺) signaling pathways serves as the "initiating trigger" of AD pathogenesis-preceding even the formation of classical Aβ plaques-a discovery that fundamentally overturns the existing cognitive framework. This study systematically deconstructs, for the first time, the cascading regulatory network of the Ca⁺/CaM-CaMKII signaling axis in AD pathology, elucidating its potential links with core AD mechanisms, including the Aβ hypothesis, tau hyperphosphorylation, Ca⁺ dyshomeostasis, synaptic dysfunction, and neuronal loss. Furthermore, this pathway not only triggers neurotoxic cascades through spatiotemporally specific regulation of synaptic Ca⁺ overload but also directly disrupts neuroplasticity-the physical basis of memory encoding-by reshaping the dynamic equilibrium between long-term potentiation (LTP) and long-term depression (LTD).Crucially, the research uncovers the dual role of CaMKII as a "molecular switch": while physiologically maintaining memory consolidation via Thr286 autophosphorylation, its pathological overactivation due to Ca⁺ dyshomeostasis leads to a "memory solidification-toxicity cycle." These findings establish a theoretical foundation for developing innovative therapies based on precise calcium signaling modulation-including Ca⁺ homeostasis intervention and CaMKII allosteric modulators-offering a potential breakthrough in overcoming the long-standing limitation of "symptom relief without targeting root causes" in AD treatment.
阿尔茨海默病（AD）是一种需要全球紧急干预的神经退行性“记忆杀手”，其核心病理机制长期以来一直笼罩在神秘之中。尽管传统的淀粉样蛋白-β（Aβ）假说仍然占据主导地位，但最近的开创性研究表明，异常钙（Ca⁺）信号通路的早期激活是AD发病机制的“起始触发因素”——甚至早于经典Aβ斑块的形成——这一发现从根本上颠覆了现有的认知框架。本研究首次系统地解构了AD病理中Ca⁺/CaM-CaMKII信号轴的级联调节网络，阐明了其与AD核心机制的潜在联系，包括Aβ假说、tau蛋白过度磷酸化、Ca⁺稳态失衡、突触功能障碍和神经元丢失。此外，该通路不仅通过对突触Ca⁺过载的时空特异性调节触发神经毒性级联反应，还通过重塑长时程增强（LTP）和长时程抑制（LTD）之间的动态平衡直接破坏神经可塑性——记忆编码的物理基础。至关重要的是，该研究揭示了CaMKII作为“分子开关”的双重作用：在生理上通过Thr286自磷酸化维持记忆巩固，而由于Ca⁺稳态失衡导致的病理过度激活则导致“记忆固化-毒性循环”。这些发现为基于精确钙信号调节开发创新疗法奠定了理论基础，包括Ca⁺稳态干预和CaMKII变构调节剂，为克服AD治疗中长期存在的“治标不治本”的局限性提供了潜在突破。
