Decreased expression of nuclear and mitochondrial DNA-encoded genes of oxidative phosphorylation in association neocortex in Alzheimer disease.

We recently reported 50% decreases in mRNA levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunits I and III in Alzheimer disease (AD) brains. The decreases were observed in an association neocortical region (midtemporal cortex) affected in AD, but not in the primary motor cortex unaffected in AD. To investigate whether the decreases are specific to mtDNA-encoded mRNA, we extended this analysis to nuclear DNA (nDNA)-encoded subunits of mitochondrial enzymes of oxidative phosphorylation (OXPHOS). Brains from five AD patients showed 50-60% decreases in mRNA levels of nDNA-encoded subunit IV of COX and the beta-subunit of the F0F1-ATP synthase in midtemporal cortex compared with mRNA levels from midtemporal cortex of control brains. In contrast, these mRNAs were not reduced in primary motor cortices of the AD brains. The amount of nDNA-encoded beta-actin mRNA and the amount of 28S rRNA were not altered in either region of the AD brain. The results suggest that coordinated decreases in expression of mitochondrial and nuclear genes occur in association cortex of AD brains and are a consequence of reduced neuronal activity and downregulation of OXPHOS machinery.