Recent results indicate that brain mitochondrial DNA (mtDNA) deletions increase with age and that these deletions are regionally variable. A 4977 basepair deletion in brain mtDNA was found to increase with age in basal ganglia, substantia nigra, and frontal cortex. In contrast few mtDNA deletions were found in cerebellum. Also levels of a 7463 basepair mtDNA deletion were found to increase with age in these brain regions. In addition, point mutations in codon 331 of brain mtDNA appear to be elevated in Alzheimer's disease. It is proposed to measure levels of brain mtDNA deletions 4977, 7463, and codon 331 point mutation in frontal cortex, medial temporal cortex, putamen, and cerebellum in brains from age-matched non-demented control subjects and Alzheimer's disease patients. Preliminary results indicate that these mtDNA deletions can be measured using a quantitative polymerase chain reaction method. It is proposed to compare normal and Alzheimer's disease brain for both the amount and regional specificity of mtDNA deletions. Attempts will be made to correlated pathological findings (e.g. plaque counts, neurofibrillary tangle counts) with the extent and distribution of mtDNA deletions. A possible source of mtDNA deletions is oxidative stress arising from inflammation. A variety of inflammatory agents stimulate cultured human astrocytoma cells to produce the cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6). IL-6 promotes aberrant neuronal differentiation and aptosis. Both IL-6 and IL-1 promote the synthesis of the Alzheimer's disease beta-amyloid precursor protein. Preliminary results suggest that cultured astrcytoma cells treated with inflammatory agents have both a marked increase in superoxide production and increased levels of mtDNA deletions. It is proposed to measure both superoxide production by cultured astrocytoma and neuronal cells, and levels of mtDNA deletions in response to inflammatory stimuli to determine if there are correlations between superoxide production and the extent of mtDNA deletions. These experiments may provide additional information on the role of inflammatory processes in the pathophysiology of Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005138-13
Application #
5204483
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
1996
Total Cost
Indirect Cost
Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302
Brenowitz, Willa D; Han, Fang; Kukull, Walter A et al. (2018) Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults. Neurobiol Aging 62:64-71
Dobbyn, Amanda; Huckins, Laura M; Boocock, James et al. (2018) Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS. Am J Hum Genet 102:1169-1184
Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin et al. (2018) Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement 14:205-214
Alosco, Michael L; Sugarman, Michael A; Besser, Lilah M et al. (2018) A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology. J Alzheimers Dis 63:1347-1360
Kinnunen, Kirsi M; Cash, David M; Poole, Teresa et al. (2018) Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study. Alzheimers Dement 14:43-53
Brent, Robert J (2018) Estimating the monetary benefits of medicare eligibility for reducing the symptoms of dementia. Appl Econ 50:6327-6340
Moreno, Cesar L; Della Guardia, Lucio; Shnyder, Valeria et al. (2018) iPSC-derived familial Alzheimer's PSEN2 N141I cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling. Mol Neurodegener 13:33
Gallagher, Damien; Kiss, Alex; Lanctot, Krista L et al. (2018) Toward Prevention of Mild Cognitive Impairment in Older Adults With Depression: An Observational Study of Potentially Modifiable Risk Factors. J Clin Psychiatry 80:
Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872

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