Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects
Wei Zhao,1,2 Jun Wang,1,2 Merina Varghese,1 Lap Ho,1,2 Paolo Mazzola,1,3 Vahram Haroutunian,2,4,5 Pavel L Katsel,2,4 Gary E Gibson,6 Samara Levine,1 Lauren Dubner,1 Giulio Maria Pasinetti1,2,4,7 1Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Geriatr...
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Dove Medical Press
2015
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oai:doaj.org-article:f88b5a94ee75469cadd571c9dc4ce8592021-12-02T06:09:47ZImpaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects1178-2021https://doaj.org/article/f88b5a94ee75469cadd571c9dc4ce8592015-03-01T00:00:00Zhttp://www.dovepress.com/impaired-mitochondrial-energy-metabolism-as-a-novel-risk-factor-for-se-peer-reviewed-article-NDThttps://doaj.org/toc/1178-2021 Wei Zhao,1,2 Jun Wang,1,2 Merina Varghese,1 Lap Ho,1,2 Paolo Mazzola,1,3 Vahram Haroutunian,2,4,5 Pavel L Katsel,2,4 Gary E Gibson,6 Samara Levine,1 Lauren Dubner,1 Giulio Maria Pasinetti1,2,4,7 1Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Geriatric Research Education Clinical Center – James J Peter VA Medical Center, Bronx, NY, USA; 3Department of Health Sciences, University of Milano-Bicocca, Monza, Italy; 4Department of Psychiatry, 5Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Department of Neurology and Neuroscience, Weill Cornell Medical College, Burke Medical Research Institute, New York, NY, USA; 7Department of Geriatrics, Icahn School of Medicine at Mount Sinai, New York, 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. Keywords: Alzheimer disease, energy metabolism, neuropathology, mitochondria, dementiaZhao WWang JVarghese MHo LMazzola PHaroutunian VKatsel PLGibson GELevine SDubner LPasinetti GMDove Medical PressarticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENNeuropsychiatric Disease and Treatment, Vol 2015, Iss default, Pp 565-574 (2015) |
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Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 |
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Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Zhao W Wang J Varghese M Ho L Mazzola P Haroutunian V Katsel PL Gibson GE Levine S Dubner L Pasinetti GM Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects |
| description |
Wei Zhao,1,2 Jun Wang,1,2 Merina Varghese,1 Lap Ho,1,2 Paolo Mazzola,1,3 Vahram Haroutunian,2,4,5 Pavel L Katsel,2,4 Gary E Gibson,6 Samara Levine,1 Lauren Dubner,1 Giulio Maria Pasinetti1,2,4,7 1Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Geriatric Research Education Clinical Center – James J Peter VA Medical Center, Bronx, NY, USA; 3Department of Health Sciences, University of Milano-Bicocca, Monza, Italy; 4Department of Psychiatry, 5Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Department of Neurology and Neuroscience, Weill Cornell Medical College, Burke Medical Research Institute, New York, NY, USA; 7Department of Geriatrics, Icahn School of Medicine at Mount Sinai, New York, 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. Keywords: Alzheimer disease, energy metabolism, neuropathology, mitochondria, dementia |
| format |
article |
| author |
Zhao W Wang J Varghese M Ho L Mazzola P Haroutunian V Katsel PL Gibson GE Levine S Dubner L Pasinetti GM |
| author_facet |
Zhao W Wang J Varghese M Ho L Mazzola P Haroutunian V Katsel PL Gibson GE Levine S Dubner L Pasinetti GM |
| author_sort |
Zhao W |
| title |
Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects |
| title_short |
Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects |
| title_full |
Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects |
| title_fullStr |
Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects |
| title_full_unstemmed |
Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects |
| title_sort |
impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects |
| publisher |
Dove Medical Press |
| publishDate |
2015 |
| url |
https://doaj.org/article/f88b5a94ee75469cadd571c9dc4ce859 |
| work_keys_str_mv |
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