| First Author | Jadiya P | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 3885 |
| PubMed ID | 31467276 | Mgi Jnum | J:279320 |
| Mgi Id | MGI:6362247 | Doi | 10.1038/s41467-019-11813-6 |
| Citation | Jadiya P, et al. (2019) Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer's disease. Nat Commun 10(1):3885 |
| abstractText | Impairments in neuronal intracellular calcium (iCa(2+)) handling may contribute to Alzheimer's disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium (mCa(2+)) signaling is a key regulator of both of these processes. Here, we report remodeling of the mCa(2+) exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired mCa(2+) efflux capacity precedes neuropathology. Neuronal deletion of the mitochondrial Na(+)/Ca(2+) 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 mCa(2+) 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 mCa(2+) exchange as potential therapeutic target in AD. |
