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Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects.

Zhao W, Wang J, Varghese M, Ho L, Mazzola P, Haroutunian V, Katsel PL, Gibson GE, Levine S, Dubner L, Pasinetti GM - Neuropsychiatr Dis Treat (2015)

Bottom Line: Recent evidence shows that Alzheimer disease (AD) dementia in the oldest-old subjects was associated with significantly less amyloid plaque and fibrillary tangle neuropathology than in the young-old population.We report a significant decrease of genes associated with mitochondrial pyruvate metabolism, the tricarboxylic acid cycle (TCA), and glycolytic pathways.Moreover, significantly higher levels of nitrotyrosylated (3-NT)-proteins and 4-hydroxy-2-nonenal (HNE) adducts, which are indexes of cellular protein oxidation and lipid peroxidation, respectively, were detected in the brains of oldest-old subjects at high risk of developing AD, possibly suggesting compensatory mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA ; Geriatric Research Education Clinical Center - James J Peter VA Medical Center, Bronx, NY, USA.

ABSTRACT
Recent evidence shows that Alzheimer disease (AD) dementia in the oldest-old subjects was associated with significantly less amyloid plaque and fibrillary tangle neuropathology than in the young-old population. In this study, using quantitative (q) PCR studies, we validated genome-wide microarray RNA studies previously conducted by our research group. We found selective downregulation of mitochondrial energy metabolism genes in the brains of oldest-old, but not young-old, AD dementia cases, despite a significant lack of classic AD neuropathology features. We report a significant decrease of genes associated with mitochondrial pyruvate metabolism, the tricarboxylic acid cycle (TCA), and glycolytic pathways. Moreover, significantly higher levels of nitrotyrosylated (3-NT)-proteins and 4-hydroxy-2-nonenal (HNE) adducts, which are indexes of cellular protein oxidation and lipid peroxidation, respectively, were detected in the brains of oldest-old subjects at high risk of developing AD, possibly suggesting compensatory mechanisms. These findings support the hypothesis that although oldest-old AD subjects, characterized by significantly lower AD neuropathology than young-old AD subjects, have brain mitochondrial metabolism impairment, which we hypothesize may selectively contribute to the development of dementia. Outcomes from this study provide novel insights into the molecular mechanisms underlying clinical dementia in young-old and oldest-old AD subjects and provide novel strategies for AD prevention and treatment in oldest-old dementia cases.

No MeSH data available.


Related in: MedlinePlus

Enzymatic activity of select TCA enzymes in the oldest-old and young-old subjects.Notes: (A) Citrate synthase and (B) malate dehydrogenase enzymatic activity in the brains (BM21 for citrate synthase; BM36 for MDH) of young-old and oldest-old subjects were measured. Results are expressed as percentage of CDR-matched normal neurological control; values represent mean ± SEM of determinations made in two independent studies; n=6 per age group per CDR; *P<0.05 by 2-tailed t-tests.Abbreviations: CDR, clinical dementia ration; YO, young-old; OO, Oldest-old; MDH, malate dehydrogenase; TCA, tricarboxylic acid cycle; SEM, standard error of mean.
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f4-ndt-11-565: Enzymatic activity of select TCA enzymes in the oldest-old and young-old subjects.Notes: (A) Citrate synthase and (B) malate dehydrogenase enzymatic activity in the brains (BM21 for citrate synthase; BM36 for MDH) of young-old and oldest-old subjects were measured. Results are expressed as percentage of CDR-matched normal neurological control; values represent mean ± SEM of determinations made in two independent studies; n=6 per age group per CDR; *P<0.05 by 2-tailed t-tests.Abbreviations: CDR, clinical dementia ration; YO, young-old; OO, Oldest-old; MDH, malate dehydrogenase; TCA, tricarboxylic acid cycle; SEM, standard error of mean.

Mentions: To assess whether the decreased expression of TCA cycle genes could also lead to decreased enzymatic activity of the TCA cycle, we performed assays for CS and MDH. We found that in normal neurological control subjects (CDR 0), there was significantly higher CS activity in oldest-old subjects compared to young-old subjects. On the other hand, in AD dementia patients, CS activity in the brain of oldest-old subjects (CDR 5) was significantly lower than CS activity in young-old subjects (Figure 4A). We found no difference in MDH activity between young-old and oldest-old subjects for either normal neurological control cases or AD dementia cases (Figure 4B).


Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects.

Zhao W, Wang J, Varghese M, Ho L, Mazzola P, Haroutunian V, Katsel PL, Gibson GE, Levine S, Dubner L, Pasinetti GM - Neuropsychiatr Dis Treat (2015)

Enzymatic activity of select TCA enzymes in the oldest-old and young-old subjects.Notes: (A) Citrate synthase and (B) malate dehydrogenase enzymatic activity in the brains (BM21 for citrate synthase; BM36 for MDH) of young-old and oldest-old subjects were measured. Results are expressed as percentage of CDR-matched normal neurological control; values represent mean ± SEM of determinations made in two independent studies; n=6 per age group per CDR; *P<0.05 by 2-tailed t-tests.Abbreviations: CDR, clinical dementia ration; YO, young-old; OO, Oldest-old; MDH, malate dehydrogenase; TCA, tricarboxylic acid cycle; SEM, standard error of mean.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356684&req=5

f4-ndt-11-565: Enzymatic activity of select TCA enzymes in the oldest-old and young-old subjects.Notes: (A) Citrate synthase and (B) malate dehydrogenase enzymatic activity in the brains (BM21 for citrate synthase; BM36 for MDH) of young-old and oldest-old subjects were measured. Results are expressed as percentage of CDR-matched normal neurological control; values represent mean ± SEM of determinations made in two independent studies; n=6 per age group per CDR; *P<0.05 by 2-tailed t-tests.Abbreviations: CDR, clinical dementia ration; YO, young-old; OO, Oldest-old; MDH, malate dehydrogenase; TCA, tricarboxylic acid cycle; SEM, standard error of mean.
Mentions: To assess whether the decreased expression of TCA cycle genes could also lead to decreased enzymatic activity of the TCA cycle, we performed assays for CS and MDH. We found that in normal neurological control subjects (CDR 0), there was significantly higher CS activity in oldest-old subjects compared to young-old subjects. On the other hand, in AD dementia patients, CS activity in the brain of oldest-old subjects (CDR 5) was significantly lower than CS activity in young-old subjects (Figure 4A). We found no difference in MDH activity between young-old and oldest-old subjects for either normal neurological control cases or AD dementia cases (Figure 4B).

Bottom Line: Recent evidence shows that Alzheimer disease (AD) dementia in the oldest-old subjects was associated with significantly less amyloid plaque and fibrillary tangle neuropathology than in the young-old population.We report a significant decrease of genes associated with mitochondrial pyruvate metabolism, the tricarboxylic acid cycle (TCA), and glycolytic pathways.Moreover, significantly higher levels of nitrotyrosylated (3-NT)-proteins and 4-hydroxy-2-nonenal (HNE) adducts, which are indexes of cellular protein oxidation and lipid peroxidation, respectively, were detected in the brains of oldest-old subjects at high risk of developing AD, possibly suggesting compensatory mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA ; Geriatric Research Education Clinical Center - James J Peter VA Medical Center, Bronx, NY, USA.

ABSTRACT
Recent evidence shows that Alzheimer disease (AD) dementia in the oldest-old subjects was associated with significantly less amyloid plaque and fibrillary tangle neuropathology than in the young-old population. In this study, using quantitative (q) PCR studies, we validated genome-wide microarray RNA studies previously conducted by our research group. We found selective downregulation of mitochondrial energy metabolism genes in the brains of oldest-old, but not young-old, AD dementia cases, despite a significant lack of classic AD neuropathology features. We report a significant decrease of genes associated with mitochondrial pyruvate metabolism, the tricarboxylic acid cycle (TCA), and glycolytic pathways. Moreover, significantly higher levels of nitrotyrosylated (3-NT)-proteins and 4-hydroxy-2-nonenal (HNE) adducts, which are indexes of cellular protein oxidation and lipid peroxidation, respectively, were detected in the brains of oldest-old subjects at high risk of developing AD, possibly suggesting compensatory mechanisms. These findings support the hypothesis that although oldest-old AD subjects, characterized by significantly lower AD neuropathology than young-old AD subjects, have brain mitochondrial metabolism impairment, which we hypothesize may selectively contribute to the development of dementia. Outcomes from this study provide novel insights into the molecular mechanisms underlying clinical dementia in young-old and oldest-old AD subjects and provide novel strategies for AD prevention and treatment in oldest-old dementia cases.

No MeSH data available.


Related in: MedlinePlus