Oligomeric amyloid β preferentially targets neuronal and not glial mitochondrial-encoded mRNAs

Alzheimers Dement. 2018 Jun;14(6):775-786. doi: 10.1016/j.jalz.2017.12.005. Epub 2018 Jan 23.

Abstract

Introduction: Our laboratories have demonstrated that accumulation of oligomeric amyloid β (OAβ) in neurons is an essential step leading to OAβ-mediated mitochondrial dysfunction.

Methods: Alzheimer's disease (AD) and matching control hippocampal neurons, astrocytes, and microglia were isolated by laser-captured microdissection from the same subjects, followed by whole-transcriptome sequencing. Complementary in vitro work was performed in OAβ-treated differentiated SH-SY5Y, followed by the use of a novel CoQ10 analogue for protection. This compound is believed to be effective both in suppressing reactive oxygen species and also functioning in mitochondrial electron transport.

Results: We report decreases in the same mitochondrial-encoded mRNAs in Alzheimer's disease laser-captured CA1 neurons and in OAβ-treated SH-SY5Y cells, but not in laser-captured microglia and astrocytes. Pretreatment with a novel CoQ10 analogue, protects neuronal mitochondria from OAβ-induced mitochondrial changes.

Discussion: Similarity of expression changes in neurons from Alzheimer's disease brain and neuronal cells treated with OAβ, and the effect of a CoQ10 analogue on the latter, suggests a pretreatment option to prevent OAβ toxicity, long before the damage is apparent.

Keywords: Alzheimer's disease; Laser capture microdissection; Mitochondria; Multifunctional radical quencher; Oligomeric amyloid β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Cell Line, Tumor
  • Female
  • Hippocampus / metabolism
  • Humans
  • In Vitro Techniques
  • Laser Capture Microdissection
  • Male
  • Microglia / drug effects
  • Microglia / metabolism
  • Microscopy, Electron, Transmission
  • Neurons / drug effects
  • Neurons / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA, Mitochondrial / genetics
  • RNA, Mitochondrial / metabolism*
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / pharmacology

Substances

  • Amyloid beta-Peptides
  • RNA, Messenger
  • RNA, Mitochondrial
  • mitochondrial messenger RNA
  • Ubiquinone
  • coenzyme Q10