Abstract
Introduction:
Alzheimer's disease (AD) features changes in mitochondrial structure and function. Investigators debate where to position mitochondrial pathology within the chronology and context of other AD features.
Methods:
To address whether mitochondrial dysfunction alters AD-implicated genes and proteins, we treated SH-SY5Y cells and induced pluripotent stem cell (iPSC)-derived neurons with chloramphenicol, an antibiotic that inhibits mtDNA-generated transcript translation. We characterized adaptive, AD-associated gene, and AD-associated protein responses.
Results:
SH-SY5Y cells and iPSC neurons responded to mtDNA transcript translation inhibition by increasing mtDNA copy number and transcription. Nuclear-expressed respiratory chain mRNA and protein levels also changed. There were AD-consistent concordant and model-specific changes in amyloid precursor protein, beta amyloid, apolipoprotein E, tau, and α-synuclein biology.
Discussion:
Primary mitochondrial dysfunction induces compensatory organelle responses, changes nuclear gene expression, and alters the biology of AD-associated genes and proteins in ways that may recapitulate brain aging and AD molecular phenomena.
Highlights:
In AD, mitochondrial dysfunction could represent a disease cause or consequence. We inhibited mitochondrial translation in human neuronal cells and neurons. Mitochondrial and nuclear gene expression shifted in adaptive-consistent patterns. APP, Aβ, APOE, tau, and α-synuclein biology changed in AD-consistent patterns. Mitochondrial stress creates an environment that promotes AD pathology.
Keywords:
Alzheimer's disease; amyloid; mitochondria; neurons; translation.