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

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.

• Authors: Magali Dumont, Daniel J Ho, Noel Y Calingasan, Hui Xu, Gary Gibson, M Flint Beal
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 47 Issue 7 Pg. 1019-27 (Oct 01 2009) ISSN: 1873-4596 [Electronic] United States
• PMID: 19596066 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amyloid beta-Peptides
• Peptide Fragments
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• Acyltransferases
• dihydrolipoamide succinyltransferase

Topics

• Acyltransferases (deficiency, metabolism)
• Alzheimer Disease (metabolism)
• Amyloid beta-Peptides (genetics, metabolism)
• Amyloidosis (metabolism, pathology, physiopathology)
• Animals
• Disease Models, Animal
• Female
• Male
• Memory Disorders (genetics, metabolism, physiopathology)
• Mice
• Mice, Transgenic
• Mitochondria (enzymology, metabolism)
• Oxidative Stress
• Peptide Fragments (genetics, metabolism)