Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease

Aging is associated with impaired mitochondrial function caused by accumula tion of oxygen free radical-induced mitochondrial (Mt) DNA mutations. One p revailing theory is that age-associated diseases, including Alzheimer's dis ease (AD), may be precipitated, propagated, or caused by impaired mitochond rial function. To investigate the role of MtDNA relative to genomic (Gn) DN A damage in AD, temporal lobe samples from postmortem AD (n = 37) and contr ol (n = 25) brains were analyzed for MtDNA and GnDNA fragmentation, mitocho ndrial protein and cytochrome oxidase expression, MitoTracker Green fluores cence (to assess mitochondrial mass/abundance), and 8-oxo-7,8-dihydro-2'-de oxyguanosine (8-OHdG) immunoreactivity. Brains with AD had more extensive n icking and fragmentation of both MtDNA and GnDNA as demonstrated by agarose gel electrophoresis, end-labeling, and the in situ terminal deoxynucleotid e transferase end-labeling (TUNEL) assay, and only the brains with AD had d etectable 8-OHdG immunoreactivity in cortical neurons. Increased MtDNA dama ge in AD was associated with reduced MtDNA content, as demonstrated by semi quantitative PCR analysis and reduced levels of Mt protein and cytochrome o xidase expression by Western blot analysis or immunohistochemical staining with image analysis. The finding of reduced MitoTracker Green fluorescence in AD brains provided additional evidence that reduced Mt mass/abundance oc curs with AD neurodegeneration. The presence of increased MtDNA and GnDNA d amage in AD suggest dual cell death cascades in AD. Impaired mitochondrial function caused by MtDNA damage may render brain cells in AD more susceptib le to oxidative injury and thereby provide a mechanism by which systemic or environmental factors could influence the course of disease.