Статья

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

Pooja JadiyaCenter for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USADevin W. KolmetzkyCenter for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USADhanendra TomarCenter for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USAAntonio Di MecoAlzheimer's Center at Temple, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USAAlyssa A. LombardiCenter for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USAJonathan P. LambertCenter for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USATimothy S. LuongoCenter for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USAMarthe H. R. LudtmannRoyal Veterinary College, 4 Royal College Street, Kings Cross, London, UKDomenico PraticòAlzheimer's Center at Temple, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USAJohn W. ElrodCenter for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA. [email protected]

2019en

ABI

Аннотация

Abstract 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.

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Идентификаторы

DOI: 10.1038/s41467-019-11813-6

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar