Dataset Information


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

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.


PROVIDER: S-EPMC6715724 | BioStudies | 2019-01-01


REPOSITORIES: biostudies

Similar Datasets

2017-01-01 | S-EPMC5731245 | BioStudies
2018-01-01 | S-EPMC6060432 | BioStudies
2020-01-01 | S-EPMC7529464 | BioStudies
2020-01-01 | S-EPMC7526387 | BioStudies
2014-01-01 | S-EPMC4269751 | BioStudies
2018-01-01 | S-EPMC5749759 | BioStudies
2020-01-01 | S-EPMC7554787 | BioStudies
1000-01-01 | S-EPMC3674348 | BioStudies
1000-01-01 | S-EPMC2732886 | BioStudies
2019-01-01 | S-EPMC6778142 | BioStudies