Mitochondrial DNA Copy Numbers in Pyramidal Neurons are Decreased and Mitochondrial Biogenesis Transcriptome Signaling is Disrupted in Alzheimer's Disease Hippocampi

Abstract

Alzheimer's disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP(+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1α were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal Aβ1-42 levels. After 48 h exposure of H9 human neural stem cells to the neurotoxic fragment Aβ25-35, mtDNA copy numbers were not significantly altered. In summary, AD postmortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD.

Aβ25–35 Suppresses Mitochondrial Biogenesis in Primary Hippocampal Neurons

“…Based on previous findings and those of the current study, there is a clear evidence that SIRT1 and PGC-1a play an important role in impaired mitochondrial biogenesis caused by Ab25-35. Consistent with previous studies (Pedros et al 2014;Rice et al 2014;Sheng et al 2012), our data show that Ab25-35 suppresses mitochondrial biogenesis factors (PGC-1a, NRF 1, NRF 2, and Tfam). We further show that Ab25-35 downregulates phosphorylation of AMPK and SIRT1 expression.…”

“…These data indicate that Ab25-35 decreases not only PGC-1a expression but also PGC-1a activity. Previous studies showed that mtDNA copy number and the expression levels of PGC-1a, NRF 1, NRF 2, and Tfam were significantly reduced in AD hippocampus and APPswe M17 cells (Pedros et al 2014;Rice et al 2014;Sheng et al 2012), which suggests that the mitochondrial biogenesis signaling is impaired in AD. Moreover, PGC-1a overexpression was shown to completely rescue whereas knockdown of PGC-1a exacerbated impaired mitochondrial biogenesis in APPswe M17 cells (Sheng et al 2012).…”

“…Recently, impaired mitochondrial biogenesis is observed in the brain of AD patients, a mouse model of AD, and APPswe M17 cells (Calkins et al 2011;Pedros et al 2014;Rice et al 2014;Sheng et al 2012). Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in AD (Sheng et al 2012).…”

Differentiation of Human Neural Stem Cells into Motor Neurons Stimulates Mitochondrial Biogenesis and Decreases Glycolytic Flux

“…MtDNA copy number was determined using multiplex qPCR targeting human mtDNA-encoded genes around the mitochondrial genome (12s rRNA, ND2, COX3, ND4) as described in previous studies [16,53]. The mtDNA standards were prepared as described previously [16].…”

Mitochondrial Function in Alzheimer’s Disease: Focus on Astrocytes

“…Baloyannis [94] described morphological alterations of the mitochondrial cristae, accumulation of osmiophilic material, and decrease of mitochondrial size to be associated with AD. The quantification of mitochondrial DNA (mtDNA) revealed low levels in AD subjects in the cortical and hippocampal areas [95,96], which may reflect a diminished number and mass of mitochondria in AD. However, a complex picture was presented by [97], where the authors demonstrated that by measuring the mtDNA present in phagosomes together with the mtDNA in healthy mitochondria the quantification resulted in higher levels in AD subjects than in controls.…”