P Jadiya
Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease
Jadiya, P; Kolmetzky, D W; Tomar, D; Di Meco, A; Lombardi, A A; Lambert, J P; Luongo, T S; Ludtmann, M H R; Praticò, D; Elrod, J W
Authors
D W Kolmetzky
D Tomar
A Di Meco
A A Lombardi
J P Lambert
T S Luongo
M H R Ludtmann
D Praticò
J W Elrod
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.
Citation
Jadiya, P., Kolmetzky, D. W., Tomar, D., Di Meco, A., Lombardi, A. A., Lambert, J. P., Luongo, T. S., Ludtmann, M. H. R., Praticò, D., & Elrod, J. W. (in press). Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease. Nature Communications, 10(3885), https://doi.org/10.1038/s41467-019-11813-6
Journal Article Type | Article |
---|---|
Acceptance Date | Aug 5, 2019 |
Deposit Date | Sep 17, 2019 |
Publicly Available Date | Oct 4, 2019 |
Journal | Nature Communications |
Electronic ISSN | 2041-1723 |
Publisher | Nature Research |
Peer Reviewed | Peer Reviewed |
Volume | 10 |
Issue | 3885 |
DOI | https://doi.org/10.1038/s41467-019-11813-6 |
Public URL | https://rvc-repository.worktribe.com/output/1380949 |
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