Mitochondria are of special interest in neurodegenerative disease because they produce large numbers of free radicals as a byproduct of producing ATP, the molecule that powers most chemical reactions in cells. Under normal conditions, these free radicals are neutralized; under disease conditions, it is hypothesized, free radicals overwhelm defense mechanisms and damage proteins, lipids, nucleic acids and other cellular components in oxidative reactions. Ironically, the mitochondria are themselves especially vulnerable to oxidative damage.

In this study, the researchers demonstrated that certain populations of neurons from AD postmortem tissue-particularly the large pyramidal neurons of the hippocampus and neocortex-have significant increases in mitochondrial DNA (mtDNA) and the mitochondrial protein cytochrome oxidase relative to other cell types in the same structures and relative to control samples. Markers of oxidative damage (8-OHG and nitrotyrosine) showed elevated damage to nucleic acids and proteins in the same neurons that showed mtDNA proliferation.

When they quantified mitochondria from biopsies of patients in the earliest stages of Alzheimer's, however, the researchers found that the vulnerable neurons have reduced numbers of intact mitochondria. The researchers note that the excess mtDNA and cytochrome oxidase in AD postmortem tissue was found outside mitochondria, in the cytoplasm or in certain lysosomes postulated to be involved on the degradation of mitochondria (by a process called autophagy). Taken together, they suggest, these observations indicate "either greater turnover of mitochondria by autophagy or a reduction of proteolytic turnover."

"That abnormalities occur in neurons lacking neurofibrillary tangles places mitochondria abnormalities as the earliest cytopathological change in AD," conclude the authors. "Other changes of AD could very well be linked to mitochondria because blockage of mitochondrial energy production shifts amyloid-β-protein precursor metabolism to the production of more amyloidgenic forms of amyloid-β. . ., induces the production of A68 antigen [the site on tau recognized by Alz-50 antibody]. . ., and activates the mitogen-activated protein kinase pathway. . ."-Hakon Heimer.

Reference:Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA. Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. Abstract