PMID- 19596066
OWN - NLM
STAT- MEDLINE
DCOM- 20100126
LR  - 20211020
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Print)
IS  - 0891-5849 (Linking)
VI  - 47
IP  - 7
DP  - 2009 Oct 1
TI  - Mitochondrial dihydrolipoyl succinyltransferase deficiency accelerates amyloid 
      pathology and memory deficit in a transgenic mouse model of amyloid deposition.
PG  - 1019-27
LID - 10.1016/j.freeradbiomed.2009.07.008 [doi]
AB  - 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.
FAU - Dumont, Magali
AU  - Dumont M
AD  - Department of Neurology and Neuroscience, Weill Cornell Medical College,New York, 
      NY 10065, USA. mad2138@med.cornell.edu
FAU - Ho, Daniel J
AU  - Ho DJ
FAU - Calingasan, Noel Y
AU  - Calingasan NY
FAU - Xu, Hui
AU  - Xu H
FAU - Gibson, Gary
AU  - Gibson G
FAU - Beal, M Flint
AU  - Beal MF
LA  - eng
GR  - P01 AG014930/AG/NIA NIH HHS/United States
GR  - P01 AG014930-08/AG/NIA NIH HHS/United States
GR  - 5P01 AG14930-08/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090722
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Peptide Fragments)
RN  - 0 (amyloid beta-protein (1-40))
RN  - 0 (amyloid beta-protein (1-42))
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 2.3.1.61 (dihydrolipoamide succinyltransferase)
SB  - IM
MH  - Acyltransferases/*deficiency/metabolism
MH  - Alzheimer Disease/metabolism
MH  - Amyloid beta-Peptides/genetics/*metabolism
MH  - Amyloidosis/metabolism/*pathology/*physiopathology
MH  - Animals
MH  - Disease Models, Animal
MH  - Female
MH  - Male
MH  - Memory Disorders/genetics/*metabolism/physiopathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Mitochondria/*enzymology/metabolism
MH  - Oxidative Stress
MH  - Peptide Fragments/genetics/*metabolism
PMC - PMC2761144
MID - NIHMS132172
EDAT- 2009/07/15 09:00
MHDA- 2010/01/27 06:00
PMCR- 2010/10/01
CRDT- 2009/07/15 09:00
PHST- 2009/05/08 00:00 [received]
PHST- 2009/07/06 00:00 [revised]
PHST- 2009/07/07 00:00 [accepted]
PHST- 2009/07/15 09:00 [entrez]
PHST- 2009/07/15 09:00 [pubmed]
PHST- 2010/01/27 06:00 [medline]
PHST- 2010/10/01 00:00 [pmc-release]
AID - S0891-5849(09)00411-0 [pii]
AID - 10.1016/j.freeradbiomed.2009.07.008 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2009 Oct 1;47(7):1019-27. doi: 
      10.1016/j.freeradbiomed.2009.07.008. Epub 2009 Jul 22.