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Peer-reviewedCC BYThe EMBO Journal

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

  • Pooja Jadiya1,2
  • E.V. Berezhnaya1
  • Devin W. Kolmetzky1
  • Dhanendra Tomar1,2
  • Henry M. Cohen1
  • Shatakshi Shukla2
  • Manfred Thomas1
  • Salman Khaledi1
  • Joanne F. Garbincius1
  • Liam Kennedy1
  • Oniel Salik1
  • Darpan Raghav2
2 more authors
  • Alycia N. Hildebrand1
  • John W. Elrod3
  1. 1Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
  2. 2Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
  3. 3Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. [email protected]
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Abstract

Loss of m Ca 2+ efflux capacity contributes to the pathogenesis and progression of Alzheimer’s disease (AD) by promoting mitochondrial Ca 2+ ( m Ca 2+ ) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of m Ca 2+ uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal m Ca 2+ 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 Ca 2+ 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 m Ca 2+ uptake represents a powerful therapeutic target to impede AD progression.

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Cite

BibTeXRIS
BibTeX
@article{jadiya2026genetic,
  title = {{Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer’s disease progression}},
  author = {Pooja Jadiya and E.V. Berezhnaya and Devin W. Kolmetzky and Dhanendra Tomar and Henry M. Cohen and Shatakshi Shukla and Manfred Thomas and Salman Khaledi and Joanne F. Garbincius and Liam Kennedy and Oniel Salik and Darpan Raghav and Alycia N. Hildebrand and John W. Elrod},
  journal = {The EMBO Journal},
  year = {2026},
  month = may,
  doi = {10.1038/s44318-026-00809-w},
  url = {https://doi.org/10.1038/s44318-026-00809-w},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer’s disease progression
AU  - Pooja Jadiya
AU  - E.V. Berezhnaya
AU  - Devin W. Kolmetzky
AU  - Dhanendra Tomar
AU  - Henry M. Cohen
AU  - Shatakshi Shukla
AU  - Manfred Thomas
AU  - Salman Khaledi
AU  - Joanne F. Garbincius
AU  - Liam Kennedy
AU  - Oniel Salik
AU  - Darpan Raghav
AU  - Alycia N. Hildebrand
AU  - John W. Elrod
PY  - 2026
DA  - 2026/05/22
JO  - The EMBO Journal
DO  - 10.1038/s44318-026-00809-w
UR  - https://doi.org/10.1038/s44318-026-00809-w
AB  - Loss of m Ca 2+ efflux capacity contributes to the pathogenesis and progression of Alzheimer’s disease (AD) by promoting mitochondrial Ca 2+ ( m Ca 2+ ) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of m Ca 2+ uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal m Ca 2+ 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 Ca 2+ 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 m Ca 2+ uptake represents a powerful therapeutic target to impede AD progression.
SN  - 0261-4189
SN  - 1460-2075
ER  -