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P4‐167: Investigation of mitochondrial DNA damage in late‐onset Alzheimer's disease
Author(s) -
Allen Mariet,
Vlachantoni Dafni,
Bisceglio Gina,
Carrasquillo Minerva,
Tulloch Brian,
Wilcox Samantha,
Hayward Caroline,
Dickson Dennis,
Wright Alan,
Younkin Steve
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.2234
Subject(s) - mitochondrial dna , biology , dna damage , cerebellum , mitochondrion , polymerase chain reaction , nuclear dna , microbiology and biotechnology , genetics , dna , gene , endocrinology
factor levels, respectively. Neurons were pre-treated for 2 days with estrogen at the low concentration of 10 pg/mL. Results: In our aging model of rat cortical neurons in common culture conditions, mitochondrial counts per neuron were found to be the same in middle-age (9-month) and old (24-month) neurons. Immunostaining for cytochrome C in individual mitochondria revealed an age-related deficit of this electron donor. Respiration measurements in middle-age and old neurons revealed no age-related changes in basal respiration, but after a glutamate stimulus, old neurons were unable to match the two-fold upregulation of respiration seen in middle-age neurons. Respiration in old neurons was inhibited by lower concentrations of potassium cyanide, suggesting a 29% deficit in functional enzyme in old compared to middle-age neurons. CCO activity in submitochondrial particles isolated from middle-age and old rat cortical neurons in culture showed no age-related differences. In addition to cytochrome C, CCO requires cardiolipin to function. Staining with nonylacridine orange revealed an age-related deficit in cardiolipin. Estrogen treatment of old neurons restored cardiolipin levels and upregulated respiration under glutamate stress. Attempts to induce mitochondrial turnover by neuronal multiplication also rejuvenated CCO activity in old neurons. Conclusions: These data suggest cytochrome C and cardiolipin levels are deficient in old neurons, preventing normal upregulation of respiration needed for oxidative phosphorylation in response to stress. Furthermore, the data suggest this deficit can be corrected with estrogen. These results provide a better understanding of the brain metabolic deficiencies that occur with age, possibly leading to susceptibility to Alzheimer’s Disease.