Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer's disease and in hereditary spinocerebellar ataxia disorders: A nonspecific change?

Controversy exists as to the clinical importance, cause, and disease specif icity of the cytochrome oxidase (CO) activity reduction observed in some pa tients with Alzheimer's disease (AD). Although it is assumed that the enzym e is present in normal amount in AD, no direct measurements of specific CO protein subunits have been conducted. We measured protein levels of CO subu nits encoded by mitochondrial (COX I, COX II) and nuclear (COX IV, COX VIc) DNA in autopsied brain of patients with AD whom we previously reported had decreased cerebral cortical CO activity. To assess disease specificity, gr oups of patients with spinocerebellar ataxia type I and Friedreich's ataxia were also included. As compared with the controls, mean protein concentrat ions of all four CO subunits were significantly decreased (-19 to -47%) in temporal and parietal cortices in the AD group but were not significantly r educed (-12 to -17%) in occipital cortex. The magnitude of the reduction in protein levels of the CO subunits encoded by mitochondrial DNA (-42 to -47 %) generally exceeded that encoded by nuclear DNA (-19 to -43%). in the spi nocerebellar ataxia disorders, COX I and COX II levels were significantly d ecreased in cerebellar cortex (-22 to -32%) but were normal or close to nor mal in cerebral cortex, an area relatively unaffected by neurodegeneration. We conclude that protein levels of mitochondrial- and nuclear-encoded CO s ubunits are moderately reduced in degenerating but not in relatively spared brain areas in AD and that the decrease is not specific to this disorder. The simplest explanation for our findings is that CO is decreased in human brain disorders as a secondary event in brain areas having reduced neuronal activity or neuronal/synaptic elements consequent to the primary neurodege nerative process.