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<p>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<sup>2</sup>⁺) 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<sup>2</sup>⁺/CaM-CaMKII signaling axis&#xa0;in AD pathology, elucidating its potential links with core AD mechanisms, including the Aβ hypothesis, tau hyperphosphorylation, Ca<sup>2</sup>⁺ dyshomeostasis, synaptic dysfunction, and neuronal loss. Furthermore, this pathway not only triggers&#xa0;neurotoxic cascades&#xa0;through spatiotemporally specific regulation of synaptic Ca<sup>2</sup>⁺ 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<sup>2</sup>⁺ 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<sup>2</sup>⁺ 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.</p>

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The Janus face of CaMKII: from memory consolidation to neurotoxic switch in Alzheimer’s disease

  • 期刊论文

  • 发表日期：

    2025年9月1日

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  • Luhong Tang,
  • Feng Liu,
  • Xuefei Sun,
  • Jiaoyan Yang,
  • Yifang Liu,
  • Xueting Pan,
  • Liying Hao,
  • Fan Lou,
  • Jingyang Su

摘要

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 (Ca2⁺) 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 Ca2⁺/CaM-CaMKII signaling axis in AD pathology, elucidating its potential links with core AD mechanisms, including the Aβ hypothesis, tau hyperphosphorylation, Ca2⁺ dyshomeostasis, synaptic dysfunction, and neuronal loss. Furthermore, this pathway not only triggers neurotoxic cascades through spatiotemporally specific regulation of synaptic Ca2⁺ 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 Ca2⁺ 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 Ca2⁺ 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.