Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer's disease hippocampi.
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.
Parkinson's Disease Center, Virginia Commonwealth University, Richmond, VA, USA Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.
Ann C
AC
Rice
Parkinson's Disease Center, Virginia Commonwealth University, Richmond, VA, USA.
Paula M
PM
Keeney
Parkinson's Disease Center, Virginia Commonwealth University, Richmond, VA, USA.
Norah K
NK
Algarzae
Parkinson's Disease Center, Virginia Commonwealth University, Richmond, VA, USA.
Amy C
AC
Ladd
Parkinson's Disease Center, Virginia Commonwealth University, Richmond, VA, USA.
Ravindar R
RR
Thomas
Parkinson's Disease Center, Virginia Commonwealth University, Richmond, VA, USA Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA.
James P
JP
Bennett
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D004167:Diphtheria Toxin / Q000494:pharmacology; D005260:Female; D018628:Gene Dosage / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D058953:Neural Stem Cells / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013223:Statistics as Topic; D059467:Transcriptome / Q000235:genetics*
D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial; D004167:Diphtheria Toxin; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C029795:diphtheria toxin fragment A
Laser capture microdissection; PGC1 alpha; TFAM; neural stem cells; real-time PCR