Ž . Molecular Brain Research 44 1997 99–104 Research report Decreased expression of nuclear and mitochondrial DNA-encoded genes of oxidative phosphorylation in association neocortex in Alzheimer disease Krish Chandrasekaran ) , Kimmo Hatanpaa, Stanley I. Rapoport, Daniel R. Brady ¨¨ Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA Accepted 23 July 1996 Abstract Ž . Ž . We recently reported 50% decreases in mRNA levels of mitochondrial DNA mtDNA -encoded cytochrome oxidase COX subunits I Ž . Ž . 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 Ž . mRNA, we extended this analysis to nuclear DNA nDNA -encoded subunits of mitochondrial enzymes of oxidative phosphorylation Ž . OXPHOS . Brains from five AD patients showed 50–60% decreases in mRNA levels of nDNA-encoded subunit IV of COX and the b-subunit of the F F -ATP synthase in midtemporal cortex compared with mRNA levels from midtemporal cortex of control brains. In 0 1 contrast, these mRNAs were not reduced in primary motor cortices of the AD brains. The amount of nDNA-encoded b-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. Keywords: Northern blot; mRNA; Mitochondria; Oxidative phosphorylation; Energy metabolism; Cerebral cortex; Brain; Alzheimer disease 1. Introduction Ž . In Alzheimer disease AD , reduction in cerebral glu- w x cose utilization is an early manifestation 8,22 . The de- crease is more pronounced and occurs earlier in associa- tion than in primary sensory and motor neocortical regions w x 10,25 . These differences reflect selective vulnerability of brain regions to AD, as neuropathological features, such as neurofibrillary tangles and senile plaques, are also found in much greater numbers in association neocortex than in primary sensory and motor cortices. Decreased brain en- ergy metabolism precedes and predicts the pattern of neu- w x ropsychological abnormalities that later appear 14,15 . We observed corresponding impairments in expression Abbreviations: OXPHOS, oxidative phosphorylation system; AD, Alzheimer disease; COX, cytochrome oxidase; TTX, tetrodotoxin; PCR, polymerase chain reaction; kb, kilobases; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; NFT, neurofibrillary tangles. ) Corresponding author. Bldg. 10, Rm. 6C 103, LNS, NIA, NIH, Ž . Bethesda, MD 20892, USA. Fax: q1 301 402-0074. of mitochondrial markers of oxidative metabolism in post- mortem brains from AD patients. These brains showed 50% decreases in levels of mRNA by Northern blots of Ž . mitochondrial DNA mtDNA -encoded subunits I and III Ž . of cytochrome oxidase COX , compared with control wx brains 3 . The decreases were observed in temporal asso- ciation neocortex, but not in primary motor cortex, and Ž corresponded to differences in neuropathology neuro- . fibrillary tangle density between the two regions. The amount of mtDNA-encoded 12S rRNA was not altered in either region of the AD brain, nor was there a difference as compared with control brain in the amount of nuclear Ž . DNA nDNA -encoded subunit B of lactate dehydrogenase Ž . LDH-B, a marker of glycolytic metabolism mRNA, or of Ž . nDNA-encoded b-actin mRNA control mRNA . The Ž amount of mtDNA also was unchanged unpublished ob- . servation . These results suggest that mRNA for mtDNA- encoded COX subunits is reduced in affected brain regions in AD, but that this reduction is not due to loss of mitochondria or mtDNA. Our recent results on in situ hybridization followed by 0169-328Xr97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. Ž . PII S0169-328X 96 00191-X