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Mitochondrial dihydrolipoyl succinyltransferase deficiency accelerates amyloid pathology and memory deficit in a transgenic mouse model of amyloid deposition.

Authors:
Dumont M, Ho DJ, Calingasan NY, Xu H, Gibson G, Beal MF
Affiliation:
Journal:
Free radical biology & medicine

Abstract

Mitochondrial dysfunction and oxidative stress are involved in Alzheimer disease (AD) pathogenesis. In human AD brains, the activity of the alpha-ketoglutarate dehydrogenase enzyme complex (alpha-KGDHC) is reduced. KGDHC is mostly involved in NADH production. It can also participate in oxidative stress and reactive oxygen species (ROS) production. The mitochondrial dihydrolipoyl succinyltransferase enzyme (DLST) is a key subunit specific to the alpha-KGDHC. In cultured cells, reduction of DLST increased H(2)O(2)-induced ROS generation and cell death. Thus, we asked whether partial genetic deletion of DLST could accelerate the onset of AD pathogenesis, using a transgenic mouse model of amyloid deposition crossed with DLST(+/-) mice. Tg19959 mice, which carry the human amyloid precursor protein with two mutations, develop amyloid deposits and progressive behavioral abnormalities. We compared Tg19959 mice to Tg19959-DLST(+/-) littermates at 2-3 months of age and studied the effects of DLST deficiency on amyloid deposition, spatial learning and memory, and oxidative stress. We found that alpha-KGDHC activity was reduced in DLST(+/-) mice. We also found that DLST deficiency increased amyloid plaque burden, Abeta oligomers, and nitrotyrosine levels and accelerated the occurrence of spatial learning and memory deficits in female Tg19959 mice. Our data suggest that alpha-KGDHC may be involved in AD pathogenesis through increased mitochondrial oxidative stress.

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