Nerve growth factor attenuates oxidant-induced β-amyloid neurotoxicity in sporadic Alzheimer's disease cybrids.
Although mitochondrial dysfunction has been linked to Alzheimer's disease (AD), it is not fully understood how this dysfunction may induce neuronal death. In this study, we show that transmitochondrial hybrid cells (cybrids) expressing mitochondrial genes from patients with sporadic AD (SAD) have substantial alterations in basal upstream tyrosine kinase signaling and downstream serine-threonine kinase signaling that are mediated by intracellular free radicals. This is associated with reduced tropomyocin receptor kinase (TrkA) and p75 neurotrophin receptor receptor expression that profoundly alters nerve growth factor signaling, increases generation of Aβ and decreases viability. Many of these observed effects in SAD cybrids would be predicted to increase risk of premature neuronal death and reduce resistance to stressors and add further support for the pathogenic role of mtDNA expression in the pathogenesis of SAD.
Onyango
Isaac G
IG
Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA. ionyango@kumc.edu
Ahn
Jin-Young
JY
Tuttle
Jeremy B
JB
Bennett
James P
JP
Swerdlow
Russell H
RH
D000111:Acetylcysteine / Q000494:pharmacology; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial; D016328:NF-kappa B; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D017475:Receptors, Nerve Growth Factor; C075222:amyloid beta-protein (1-42); D014443:Tyrosine; D020917:Receptor, trkA; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; D000111:Acetylcysteine