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Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease

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Listed:
  • Pooja Jadiya

    (Lewis Katz School of Medicine at Temple University)

  • Devin W. Kolmetzky

    (Lewis Katz School of Medicine at Temple University)

  • Dhanendra Tomar

    (Lewis Katz School of Medicine at Temple University)

  • Antonio Meco

    (Lewis Katz School of Medicine at Temple University
    Lewis Katz School of Medicine at Temple University)

  • Alyssa A. Lombardi

    (Lewis Katz School of Medicine at Temple University)

  • Jonathan P. Lambert

    (Lewis Katz School of Medicine at Temple University)

  • Timothy S. Luongo

    (Lewis Katz School of Medicine at Temple University)

  • Marthe H. Ludtmann

    (Royal Veterinary College)

  • Domenico Praticò

    (Lewis Katz School of Medicine at Temple University
    Lewis Katz School of Medicine at Temple University)

  • John W. Elrod

    (Lewis Katz School of Medicine at Temple University)

Abstract

Impairments in neuronal intracellular calcium (iCa2+) handling may contribute to Alzheimer’s disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium (mCa2+) signaling is a key regulator of both of these processes. Here, we report remodeling of the mCa2+ exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired mCa2+ efflux capacity precedes neuropathology. Neuronal deletion of the mitochondrial Na+/Ca2+ exchanger (NCLX, Slc8b1 gene) accelerated memory decline and increased amyloidosis and tau pathology. Further, genetic rescue of neuronal NCLX in 3xTg-AD mice is sufficient to impede AD-associated pathology and memory loss. We show that mCa2+ overload contributes to AD progression by promoting superoxide generation, metabolic dysfunction and neuronal cell death. These results provide a link between the calcium dysregulation and metabolic dysfunction hypotheses of AD and suggest mCa2+ exchange as potential therapeutic target in AD.

Suggested Citation

  • Pooja Jadiya & Devin W. Kolmetzky & Dhanendra Tomar & Antonio Meco & Alyssa A. Lombardi & Jonathan P. Lambert & Timothy S. Luongo & Marthe H. Ludtmann & Domenico Praticò & John W. Elrod, 2019. "Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11813-6
    DOI: 10.1038/s41467-019-11813-6
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