Elsevier

Molecular Brain Research

Volume 44, Issue 1, February 1997, Pages 99-104
Molecular Brain Research

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

https://doi.org/10.1016/S0169-328X(96)00191-XGet rights and content

Abstract

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 β-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 β-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.

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

References (34)

  • Anderson, S., Bankier, A.T., Barrell, B.G., de Bruijn, M.H.L., Coulson, A.R., Drouin, J., Eperon, I.C., Nierlich, D.P.,...
  • Chandrasekaran, K., Stoll, J., Giordano, T., Atack, J.R., Matocha, M.F., Brady, D.R. and Rapoport, S.I., Differential...
  • Chandrasekaran, K., Giordano, T., Brady, D.R., Stoll, J., Martin, L.J. and Rapoport, S.I., Impairment in mitochondrial...
  • Chandrasekaran, K., Giordano, T., Stoll, J., Brady, D.R., Hatanpää, K., Martin, L.J. and Rapoport, S.I., Impairment in...
  • Chirgwin, J.M., Przybyla, A.E., MacDonald, R.J. and Rutter, W.J., Isolation of biologically active ribonucleic acid...
  • DeKosky, S.T. and Scheff, S.W., Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with...
  • Dorsman, J.C., van Heeswijk, W.C. and Grivell, L.A., Identification of two factors which bind to the upstream sequences...
  • Duara, R., Grady, C., Haxby, J., Sundaram, M., Cutler, N.R., Heston, L., Moore, A., Schlageter, N., Larson, S. and...
  • Fukuyama, R., Hatanpää, K., Rapoport, S.I. and Chandrasekaran, K., Gene expression of ND4, a subunit of complex I of...
  • Grady, C.L., Haxby, J.V., Horwitz, B., Berg, G. and Rapoport, S.I., Neuropsychological and cerebral metabolic function...
  • Guarente, L., Regulatory proteins in yeast, Annu. Rev. Genet., 21 (1987)...
  • Guntern, R., Bouras, C., Hof, P.R. and Vallet, P.G., An improved thioflavine S method for staining neurofibrillary...
  • Hatanpää, K., Brady, D.R., Stoll, J., Rapoport, S.I. and Chandrasekaran, K., Neuronal activity and early...
  • Haxby, J.V., Grady, C.L., Duara, R., Schlageter, N., Berg, G. and Rapoport, S.I., Neocortical metabolic abnormalities...
  • Haxby, J.V., Grady, C.L., Koss, E., Horwitz, B., Heston, L., Schapiro, M., Friedland, R.P. and Rapoport, S.I.,...
  • Heddi, A., Lestienne, P., Wallace, D.C. and Stepien, G., Mitochondrial DNA expression in mitochondrial myopathies and...
  • Heddi, A., Lestienne, P., Wallace, D.C. and Stepien, G., Steady state levels of mitochondrial and nuclear oxidative...
  • Cited by (78)

    • Pathophysiology in the comorbidity of Bipolar Disorder and Alzheimer's Disease: pharmacological and stem cell approaches

      2018, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      Post-mortem analyses of AD brain have shown differential expression of mitochondria genes (Perry et al., 1980) and alterations in mitochondria morphology and distribution (Wang et al., 2008; Wang et al., 2009a,). In addition, decreased expression of nuclear or mitochondrial genes coding for the oxidative phosphorylation pathway was detected by real-time imaging of the cortex of AD patients, correlating with diminished glucose metabolism, observed by positron emission tomography (Chandrasekaran et al., 1997, 1996). Mitochondrial dysfunction is one of the earliest features of AD, resulting in generation of ROS (Du et al., 2010; Yao et al., 2011; Zhu et al., 2013).

    • Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression

      2013, Toxicology and Applied Pharmacology
      Citation Excerpt :

      Decrease in mRNA fold changes was higher for subunit 1 compared to all other subunits studied, suggesting that subunit 1 is critical for complex I of OXPHOS. Our findings of the down-regulation of complex I subunits are also in agreement with earlier studies (Aksenov et al., 1999; Chandrasekaran et al., 1997; Fukuyama et al., 1996). In the present study, there was no significant difference in the mRNA level of SDH2, which is a nuclear encoded subunit of complex 2, in the HC and CS regions of rat brain in aluminium treated rats compared to control (Fig. 3).

    View all citing articles on Scopus
    View full text