1 May 2001. A closer look at mitochondria in Alzheimer's disease
confirms that oxidative damage to these cellular power plants is a
central feature of the disease, according to a report in the May 1 issue
of the Journal of Neuroscience. The study, led by researchers at Case
Western Reserve University in Cleveland, Ohio, showed that the neurons most
vulnerable in Alzheimer's are also the most likely to show mitochondrial
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