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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

Nitrotyrosylated (3-NT)-proteins and protein-bound HNE levels are differentially elevated in the brains of oldest-old MCI cases relative to young-old MCI cases.Notes: Protein oxidation levels were measured in postmortem (BM 9) brain samples. (A) Representative image of HNE immunoreactivity. (B) Comparison of lipid oxidation levels as a function of clinical dementia in the two age groups. (C) Comparison of protein oxidation levels as a function of clinical dementia in the two age groups. Results are expressed as percentage of age-matched CDR 0 subjects; values represent means ± SEM of determinations made in two independent studies; n=6 per age group per CDR; *P<0.05, versus control group.Abbreviations: HNE, 4-hydroxy-2-nonenal; 3-NT, 3-nitrotyrosine; CDR, clinical dementia rating; MCI, mild cognitive impairment (CDR 0.5); SEM, standard error of mean.
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f5-ndt-11-565: Nitrotyrosylated (3-NT)-proteins and protein-bound HNE levels are differentially elevated in the brains of oldest-old MCI cases relative to young-old MCI cases.Notes: Protein oxidation levels were measured in postmortem (BM 9) brain samples. (A) Representative image of HNE immunoreactivity. (B) Comparison of lipid oxidation levels as a function of clinical dementia in the two age groups. (C) Comparison of protein oxidation levels as a function of clinical dementia in the two age groups. Results are expressed as percentage of age-matched CDR 0 subjects; values represent means ± SEM of determinations made in two independent studies; n=6 per age group per CDR; *P<0.05, versus control group.Abbreviations: HNE, 4-hydroxy-2-nonenal; 3-NT, 3-nitrotyrosine; CDR, clinical dementia rating; MCI, mild cognitive impairment (CDR 0.5); SEM, standard error of mean.

Mentions: To gain insight into the potential changes in oxidative stress and mitochondrial energy metabolism in the progression of AD, we used a dot-blot approach (Figure 5A) to explore global lipid peroxidation and protein oxidation profiles in the same brain region (BM 9) of young-old and oldest-old AD dementia subjects relative to normal neurological control subjects. Surprisingly, we found significantly higher levels of HNE adducts (Figure 5B) and 3-NT-proteins (Figure 5C), which are indexes of lipid peroxidation and cellular protein oxidation, respectively, in the brains of oldest-old subjects at high risk for developing AD dementia (mild cognitive impairment, MCI; CDR 0.5). Lastly, we noticed that accumulation of HNE and 3-NT oxidative proteins eventually reaches a plateau in both the young-old and oldest-old cases as a function of clinical dementia (Figure 5B and C).


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)

Nitrotyrosylated (3-NT)-proteins and protein-bound HNE levels are differentially elevated in the brains of oldest-old MCI cases relative to young-old MCI cases.Notes: Protein oxidation levels were measured in postmortem (BM 9) brain samples. (A) Representative image of HNE immunoreactivity. (B) Comparison of lipid oxidation levels as a function of clinical dementia in the two age groups. (C) Comparison of protein oxidation levels as a function of clinical dementia in the two age groups. Results are expressed as percentage of age-matched CDR 0 subjects; values represent means ± SEM of determinations made in two independent studies; n=6 per age group per CDR; *P<0.05, versus control group.Abbreviations: HNE, 4-hydroxy-2-nonenal; 3-NT, 3-nitrotyrosine; CDR, clinical dementia rating; MCI, mild cognitive impairment (CDR 0.5); SEM, standard error of mean.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4356684&req=5

f5-ndt-11-565: Nitrotyrosylated (3-NT)-proteins and protein-bound HNE levels are differentially elevated in the brains of oldest-old MCI cases relative to young-old MCI cases.Notes: Protein oxidation levels were measured in postmortem (BM 9) brain samples. (A) Representative image of HNE immunoreactivity. (B) Comparison of lipid oxidation levels as a function of clinical dementia in the two age groups. (C) Comparison of protein oxidation levels as a function of clinical dementia in the two age groups. Results are expressed as percentage of age-matched CDR 0 subjects; values represent means ± SEM of determinations made in two independent studies; n=6 per age group per CDR; *P<0.05, versus control group.Abbreviations: HNE, 4-hydroxy-2-nonenal; 3-NT, 3-nitrotyrosine; CDR, clinical dementia rating; MCI, mild cognitive impairment (CDR 0.5); SEM, standard error of mean.
Mentions: To gain insight into the potential changes in oxidative stress and mitochondrial energy metabolism in the progression of AD, we used a dot-blot approach (Figure 5A) to explore global lipid peroxidation and protein oxidation profiles in the same brain region (BM 9) of young-old and oldest-old AD dementia subjects relative to normal neurological control subjects. Surprisingly, we found significantly higher levels of HNE adducts (Figure 5B) and 3-NT-proteins (Figure 5C), which are indexes of lipid peroxidation and cellular protein oxidation, respectively, in the brains of oldest-old subjects at high risk for developing AD dementia (mild cognitive impairment, MCI; CDR 0.5). Lastly, we noticed that accumulation of HNE and 3-NT oxidative proteins eventually reaches a plateau in both the young-old and oldest-old cases as a function of clinical dementia (Figure 5B and C).

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