Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Saravanan S. Karuppagounder, Hui Xu, Qingli Shi, Lian H. Chen, Steve Pedrini, David Pechman, Harriet Baker, M. Flint Beal, Sam E. Gandy, Gary E. Gibson

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

Mitochondrial dysfunction, oxidative stress and reductions in thiamine-dependent enzymes have been implicated in multiple neurological disorders including Alzheimer's disease (AD). Experimental thiamine deficiency (TD) is an established model for reducing the activities of thiamine-dependent enzymes in brain. TD diminishes thiamine-dependent enzymes throughout the brain, but produces a time-dependent selective neuronal loss, glial activation, inflammation, abnormalities in oxidative metabolism and clusters of degenerating neurites in only specific thalamic regions. The present studies tested how TD alters brain pathology in Tg19959 transgenic mice over expressing a double mutant form of the amyloid precursor protein (APP). TD exacerbated amyloid plaque pathology in transgenic mice and enlarged the area occupied by plaques in cortex, hippocampus and thalamus by 50%, 200% and 200%, respectively. TD increased Aβ1-42 levels by about three fold, β-CTF (C99) levels by 33% and β-secretase (BACE1) protein levels by 43%. TD-induced inflammation in areas of plaque formation. Thus, the induction of mild impairment of oxidative metabolism, oxidative stress and inflammation induced by TD alters metabolism of APP and/or Aβ and promotes accumulation of plaques independent of neuron loss or neuritic clusters.

Original languageEnglish
Pages (from-to)1587-1600
Number of pages14
JournalNeurobiology of Aging
Volume30
Issue number10
DOIs
StatePublished - Oct 2009
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Aβ peptide
  • Energy metabolism
  • KGDHC
  • Mild oxidative impairment
  • Mitochondria
  • Thiamine deficiency

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