Effect of age on behavioral and enzymatic changes during thiamin deficiency

Freeman, G. B.; Nielsen, Pamela; Gibson, Gary E.

doi:10.1016/0197-4580(87)90037-6

Cited by 24 publications

(19 citation statements)

References 22 publications

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“…Brain KGDHC activity from aged animals shows enhanced sensitivity toward metabolic insults (ie, thiamine deficiency) that lead to oxidative stress. 43 Age-dependent reperfusion-induced reductions in mitochondrial function may relate to the sensitivity of KGDHC activity to HNE. 44 Thus, a variety of evidence suggests that the sensitivity of KGDHC activity to metabolic stress, including HNE, may make KGDHC activity a link between oxidative stress, cognitive deficits, and neuropathological findings in AD.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype

et al. 2000

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Brain metabolism and the activity of the α‐ketoglutarate dehydrogenase complex (KGDHC), a mitochondrial enzyme, are diminished in brains from patients with Alzheimer's disease (AD). In 109 subjects, the Clinical Dementia Rating (CDR) score was highly correlated with brain KGDHC activity. In AD patients who carried the epsilon 4 allele of the apolipoprotein E gene (ApoE4), the CDR score correlated better with KGDHC activity than with the densities of neuritic plaques or neuritic tangles. In contrast, in patients without ApoE4, the CDR score correlated significantly better with tangles and plaques than with KGDHC activity. The results suggest that mitochondrial/oxidative damage may be more important for the cognitive dysfunction in AD patients who carry ApoE4 than in those who do not. Ann Neurol 2000;48:297–303

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Section: Discussionmentioning

confidence: 99%

Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype

et al. 2000

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“…TD does alter open field behavior in mice. For example, a 37% and 39% decline in total distance and numbers of vertical movements occurs by day 7 of TD, respectively (Freeman et al, 1987). Rotarod performance is a reproducible and simple behavioral task.…”

Section: Discussionmentioning

confidence: 99%

“…Single time point measures suggest that TD-induced deficits in open field behavior correlate to decreases in whole brain KGDHC activity (Freeman et al, 1987). The majority of these studies has been performed in rats, involve labor intensive protocols that are difficult to replicate and the temporal appearance of changes in these measures does not parallel changes in SmTN.…”

Section: Introductionmentioning

confidence: 99%

“…TD diminishes KGDHC activity in whole brain homogenates (Freeman et al, 1987;Bubber et al, 2004) or dissected brain regions such as cerebral cortex, entire thalamus or inferior colliculus (Butterworth et al, 1986;Sheu et al, 1998). For these brain regions, the changes in in vitro glucose flux reflected selective vulnerability better than KGDHC activity (Gibson et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

“…Thiamine deficiency (TD) in rodents induces mild oxidative stress, microglial activation, selective neuronal cell death, diminished energy metabolism and behavioral abnormalities (Langlais et al, 1997;Calingasan et al, 1999Calingasan et al, , 2000Hakim and Pappius, 1981;Gibson et al, 1982;Freeman et al, 1987) that model important aspects of a number of neurodegenerative diseases including Alzheimer's disease (AD) Zhang, 2001, 2002a), Parkinson's disease (PD) (Schwab et al, 1996;Gibson et al, 2003), progressive supranuclear palsy (Park et al, 2001) and Wernicke-Korsakoff's syndrome (Victor et al, 1989). Diminished activities of thiamine dependent-enzymes such as the α-ketoglutarate dehydrogenase complex (KGDHC) have been consistently observed in brains of TD animal models and in post mortem brains of humans with age-related diseases (Sheu et al, 1998;Gibson et al, 1999;Mastrogiacoma et.…”

Section: Introductionmentioning

confidence: 99%

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Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability

Shi

Karuppagounder

et al. 2007

Neurochemistry International

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Thiamine-dependent enzymes are diminished in multiple neurodegenerative diseases. Thiamine deficiency (TD) reduces the activity of thiamine dependent-enzymes [e.g., the α-ketoglutarate dehydrogenase complex (KGDHC)], induces regional selective neurodegeneration and serves as a model of a mild impairment of oxidative metabolism. The current experiments tested whether changes in KGDHC protein subunits (E1k, E2k and E3) or activity or message levels underlie the selective loss of neurons in particular brain regions. Thus, TD-induced changes in these variables in the brain region most vulnerable to TD [the sub-medial thalamic nucleus (SmTN)] were compared to those in a region that is relatively resistant to TD (cortex) at stages of TD when the neuron loss in SmTN is not present, minimal or severe. Impaired motor performance on rotarod was apparent by 8 days of TD (-32%) and was severe by 10 days of TD (-97%). At TD10, the overall KGDHC activity measured by an in situ histochemical staining method declined 52% in SmTN but only 20% in cortex. Reductions in the E2k and E3 mRNA in SmTN occurred as early as TD6 (-28% and -18%, respectively) and were more severe by TD10 (-61% and -66%, respectively). On the other hand, the level of E1k mRNA did not decline in SmTN until TD10 (-48%). In contrast, TD did not alter mRNA levels of the subunits in cortex at late stages. Western blots and immunocytochemistry revealed different aspects of the changes in protein levels. In SmTN, the immunoreactivity of E1k and E3 by Western blotting increased 34% and 40%, respectively, only at TD8. In cortex, the immunoreactivity of the three subunits was not altered. Immunocytochemical staining of brain sections from TD10 mice indicated a reduction in the immunoreactivity of all subunits in SmTN, but not in cortex. These findings demonstrate that the response of the KGDHC activity, mRNA and immunoreactivity of E1k, E2k and E3 to TD is region-and time-dependent. Loss of KGDHC activity in cortex is likely related to post-translational modification rather than a loss of protein, whereas in SmTN transcriptional and post-translational modifications may account for diminished KGDHC activity. Moreover, the earlier detection in TD induced-changes of the transcripts of KGDHC indicates that transcriptional modification of the two subunits (E2k and E3) of KGDHC may be one of the early events in the cascade leading to selective neuronal death.

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Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype

Gibson¹,

Haroutunian²,

Zhang³

et al. 2000

Ann Neurol.

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Brain metabolism and the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a mitochondrial enzyme, are diminished in brains from patients with Alzheimer's disease (AD). In 109 subjects, the Clinical Dementia Rating (CDR) score was highly correlated with brain KGDHC activity. In AD patients who carried the epsilon 4 allele of the apolipoprotein E gene (ApoE4), the CDR score correlated better with KGDHC activity than with the densities of neuritic plaques or neuritic tangles. In contrast, in patients without ApoE4, the CDR score correlated significantly better with tangles and plaques than with KGDHC activity. The results suggest that mitochondrial/oxidative damage may be more important for the cognitive dysfunction in AD patients who carry ApoE4 than in those who do not.

show abstract

Effect of age on behavioral and enzymatic changes during thiamin deficiency

Cited by 24 publications

References 22 publications

Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype

Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype

Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability

Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype

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