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.
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This post is Copyright: Alexander P. Gabrielli,
Lesya Novikova,
Amol Ranjan,
Xiaowan Wang,
Nicholas J. Ernst,
Dhanushki Abeykoon,
Anysja Roberts,
Annie Kopp,
Clayton Mansel,
Linlan Qiao,
Colton R. Lysaker,
Ian W. Wiedling,
Heather M. Wilkins,
Russell H. Swerdlow | October 23, 2024