title: Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects.
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.
authors.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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.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.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Merina
authors.initials: M
authors.lastname: Varghese
authors.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.
authors.forename: Lap
authors.initials: L
authors.lastname: Ho
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA ; Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mazzola
authors.affiliation: Geriatric Research Education Clinical Center - James J Peter VA Medical Center, Bronx, NY, USA ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA ; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Geriatric Research Education Clinical Center - James J Peter VA Medical Center, Bronx, NY, USA ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Pavel L
authors.initials: PL
authors.lastname: Katsel
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, Burke Medical Research Institute, New York, NY, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gibson
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Samara
authors.initials: S
authors.lastname: Levine
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Dubner
authors.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 ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA ; Department of Geriatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Giulio Maria
authors.initials: GM
authors.lastname: Pasinetti
keywords: Alzheimer disease; dementia; energy metabolism; mitochondria; neuropathology