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Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease
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Journal Article
Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease
2019
Overview
Impairments in neuronal intracellular calcium (
i
Ca
2+
) handling may contribute to Alzheimer’s disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium (
m
Ca
2+
) signaling is a key regulator of both of these processes. Here, we report remodeling of the
m
Ca
2+
exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired
m
Ca
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
m
Ca
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
m
Ca
2+
exchange as potential therapeutic target in AD.
Dysregulation of intracellular calcium is reported in Alzheimer’s disease. Here the authors show that loss of the mitochondrial Na
+
/Ca
2
+
exchanger, NCLX – primary route of mitochondrial calcium efflux, precedes neuronal pathology in experimental models and contributes to Alzheimer’s disease progression.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ 13/109
/ 13/44
/ 13/51
/ 14
/ 14/10
/ 14/19
/ 14/34
/ 38
/ 45
/ 45/22
/ 64
/ 64/60
/ 82/80
/ 96
/ 96/2
/ Alzheimer Disease - metabolism
/ Animals
/ Calcium
/ Efflux
/ Female
/ Humanities and Social Sciences
/ Mice
/ Science
/ Sodium-Calcium Exchanger - genetics
