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<p>Loss of <sub>m</sub>Ca<sup>2+</sup> efflux capacity contributes to the pathogenesis and progression of Alzheimer’s disease (AD) by promoting mitochondrial Ca<sup>2+</sup> (<sub>m</sub>Ca<sup>2+</sup>) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of <sub>m</sub>Ca<sup>2+</sup> uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal <sub>m</sub>Ca<sup>2+</sup> uptake reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline in 3xTg-AD mice. Knockdown of <i>Mcu</i> in an in vitro model of AD significantly reduced matrix Ca<sup>2+</sup> content, redox imbalance, and mitochondrial dysfunction. The preservation of mitochondrial function rescued the AD-dependent decline in autophagic capacity and protected neurons against amyloidosis and cell death. This was corroborated by in vivo data showing improved mitochondrial structure and apposition in AD mice with loss of neuronal <i>Mcu</i>. These results suggest that inhibition of neuronal <sub>m</sub>Ca<sup>2+</sup> uptake represents a powerful therapeutic target to impede AD progression.</p>

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Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer’s disease progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月22日

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  • Pooja Jadiya,
  • Elena Berezhnaya,
  • Devin W Kolmetzky,
  • Dhanendra Tomar,
  • Henry M Cohen,
  • Shatakshi Shukla,
  • Manfred Thomas,
  • Salman Khaledi,
  • Joanne F Garbincius,
  • Liam Kennedy,
  • Oniel Salik,
  • Darpan Raghav,
  • Alycia N Hildebrand,
  • John W Elrod

摘要

Loss of mCa2+ efflux capacity contributes to the pathogenesis and progression of Alzheimer’s disease (AD) by promoting mitochondrial Ca2+ (mCa2+) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of mCa2+ uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal mCa2+ uptake reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline in 3xTg-AD mice. Knockdown of Mcu in an in vitro model of AD significantly reduced matrix Ca2+ content, redox imbalance, and mitochondrial dysfunction. The preservation of mitochondrial function rescued the AD-dependent decline in autophagic capacity and protected neurons against amyloidosis and cell death. This was corroborated by in vivo data showing improved mitochondrial structure and apposition in AD mice with loss of neuronal Mcu. These results suggest that inhibition of neuronal mCa2+ uptake represents a powerful therapeutic target to impede AD progression.