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Quantitative Analysis of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Stabilization in a Neural Model of Alzheimer's Disease (AD)
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ER stress-mediated apoptotic pathway induced by Abeta peptide requires the presence of functional mitochondria

Rui O Costa1, Elisabete Ferreiro, Sandra M Cardoso

  • 1Faculty of Medicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.

Journal of Alzheimer'S Disease : JAD
|February 26, 2010
PubMed

Insights

Amyloid-beta peptide triggers Alzheimer's disease cell death by disrupting endoplasmic reticulum (ER) and mitochondria. Functional mitochondria are essential for this ER-mitochondria crosstalk-mediated apoptosis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Amyloid-beta (Abeta) peptide is implicated in Alzheimer's disease (AD) pathogenesis.
  • Abeta induces mitochondrial and endoplasmic reticulum (ER) dysfunction, leading to apoptosis.
  • ER-mitochondria crosstalk is a critical factor in cellular response to stress.

Purpose of the Study:

  • To investigate the role of ER-mitochondria crosstalk in Abeta-induced apoptotic cell death.
  • To determine if functional mitochondria are required for ER stress-mediated apoptosis triggered by Abeta.

Main Methods:

  • Utilized mitochondrial DNA-depleted rho0 cells and parental rho+ cells.
  • Treated cells with synthetic Abeta1-40 peptide and ER stressors (thapsigargin, brefeldin A).
  • Assessed ER stress markers (GRP78, caspase activity, ER calcium stores), pro-apoptotic factors (GADD153/CHOP), and apoptosis (TUNEL assay, caspase-9, -3 activation).

Main Results:

  • Abeta and ER stressors increased GRP78 expression, caspase activity, and depleted ER calcium stores.
  • Functional mitochondria were required for ER stress-mediated apoptotic cell death induced by Abeta.
  • Increased GADD153/CHOP, caspase-9/-3 activation, and TUNEL-positive cells were observed in rho+ cells but abolished in rho0 cells.

Conclusions:

  • There is a close communication between ER and mitochondria during Abeta-induced apoptotic cell death.
  • Mitochondria are essential for the molecular cascade of cell death in AD pathogenesis.
  • Findings provide insights into the mechanisms of cell death in Alzheimer's disease.

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