Research reportDecreased expression of nuclear and mitochondrial DNA-encoded genes of oxidative phosphorylation in association neocortex in Alzheimer disease
Introduction
In Alzheimer disease (AD), reduction in cerebral glucose utilization is an early manifestation 8, 22. The decrease is more pronounced and occurs earlier in association than in primary sensory and motor neocortical regions 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 energy metabolism precedes and predicts the pattern of neuropsychological abnormalities that later appear 14, 15.
We observed corresponding impairments in expression of mitochondrial markers of oxidative metabolism in postmortem brains from AD patients. These brains showed 50% decreases in levels of mRNA by Northern blots of mitochondrial DNA (mtDNA)-encoded subunits I and III of cytochrome oxidase (COX), compared with control brains [3]. The decreases were observed in temporal association neocortex, but not in primary motor cortex, and corresponded to differences in neuropathology (neurofibrillary 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 DNA (nDNA)-encoded subunit B of lactate dehydrogenase (LDH-B, a marker of glycolytic metabolism) mRNA, or of nDNA-encoded β-actin mRNA (control mRNA). The amount of mtDNA also was unchanged (unpublished observation). 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 staining for paired helical filaments indicate that a decrease in COX subunit III mRNA precedes formation of neurofibrillary tangles (NFTs) in AD pyramidal neurons in midtemporal cortex, and that COX mRNA further decreases as NFT formation progresses [13].
Human mtDNA encodes 13 polypeptides (COX I, COX II, COX III: subunits I, II and III of cytochrome c-oxidase; cyt b: apocytochrome b; ATPase 6 and ATPase 8: subunits 6 and 8 of H+-ATPase; ND1, ND2, ND3, ND4, ND4L, ND5 and ND6: subunits 1, 2, 3, 4, 4L, 5 and 6 of NADH dehydrogenase); 2 ribosomal (12S rRNA and 16S rRNA) and 22 transfer RNAs [1]. A number of other polypeptides, encoded by nDNA, are imported into mitochondria. Some of these, such as the subunit IV of COX (COX IV) and the β-subunit of the F0F1-ATP synthase (ATPsynβ), are assembled with the mtDNA-encoded subunit polypeptides to form four of the five enzyme complexes (complexes I–V) of the oxidative phosphorylation (OXPHOS) system 20, 24, 29, 34. Synthesis and assembly of the subunit polypeptides of the OXPHOS system require coordinated expression of the mtDNA- and nDNA-encoded genes [20]. There are indications that coordinated transcriptional regulation of nDNA- and mtDNA-encoded subunits of OXPHOS enzyme complexes is achieved through certain cis elements and trans-acting factors 7, 11, 20.
To investigate whether the decreases in mRNA for mitochondrial enzymes of OXPHOS are specific to mtDNA-encoded subunits, we extended our analysis to nDNA-encoded subunits of OXPHOS enzymes. An abstract of this work has been published [4].
Section snippets
Brain tissue samples and evaluation of neuronal pathology
Postmortem samples from the midtemporal gyrus (Brodmann area 21) and primary motor cortex (Brodmann area 4) were obtained from brains of 5 AD patients and 5 age-matched healthy controls. Autopsies were performed within 24 h of death, with a mean (±S.E.M.) postmortem delay of 9.6±3.2 h for the AD patients and of 7.2±1.0 h for the control subjects (difference not statistically significant). Control subjects (2 males and 3 females) were 73–89 years old (82.6±2.8 years). AD patients (2 males and 3
Distribution of neuronal pathology in motor and midtemporal cortices of control and AD brains
The tangle and plaque counts in each AD and control case in midtemporal and motor cortices have been published (Table 1 in [3]). There were significantly more neurofibrillary tangles and senile plaques in midtemporal cortices of AD cases compared with control midtemporal cortices. Within the AD cases, midtemporal cortex contained significantly more tangles and plaques than motor cortex. There was no significant difference in tangle or plaque counts between AD and control motor cortices. This is
Coordinated expression of nuclear and mitochondrial genes for the OXPHOS system
The decreases in expression of COX IV, ATPsynβ and ND1 genes, but not of 28S rRNA, may be due to factors that regulate expression of nuclear and mitochondrial genes encoding for the OXPHOS system. The OXPHOS system in mammals consists of five multisubunit complexes [29]. Four of these complexes are bipartite, consisting of some subunits encoded by mtDNA and others by nDNA [29]. Recent studies suggest that coordinated expression of nuclear and mitochondrial genes for the OXPHOS system is
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