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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein

Published on: January 2, 2015

Mitophagy Failure in APP and Tau Overexpression Model of Alzheimer's Disease

Patricia Martín-Maestro1,2, Ricardo Gargini1,3, Esther García1

  • 1Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Cantoblanco, Madrid, Spain.

Journal of Alzheimer'S Disease : JAD
|July 1, 2019
PubMed

Insights

Alzheimer's disease involves mitochondrial dysfunction. Overexpressing amyloid-β protein precursor (AβPP) and tau proteins impairs mitophagy, the process of clearing damaged mitochondria, mimicking disease pathology.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Mitochondrial dysfunction and oxidative stress are hallmarks of Alzheimer's disease (AD).
  • Autophagy, a cellular recycling process, is altered in sporadic AD.
  • The specific roles of amyloid-β protein precursor (AβPP) and tau in mitophagy defects in AD are not fully understood.

Purpose of the Study:

  • To investigate the contribution of AβPP and tau to mitophagy impairment in Alzheimer's disease.
  • To determine if AβPP and tau overexpression recapitulates mitophagy failure observed in sporadic AD.

Main Methods:

  • Human fibroblasts were genetically modified using lentivectors to overexpress APP and Tau.
  • Cells were treated with CCCP (a mitochondrial uncoupler) to induce mitophagy.
  • Mitophagy flux, mitochondrial labeling (PINK1, PARK2), and mitochondrial membrane potential were assessed.

Main Results:

  • Both AβPP and tau individually enhanced overall autophagy flux, primarily by increasing degradation.
  • However, mitophagy specifically showed reduced labeling of mitochondria by PINK1 and PARK2, indicating impaired clearance.
  • Combined overexpression of AβPP and tau led to significant mitophagy functional impairment, evidenced by accumulated depolarized mitochondria.

Conclusions:

  • Overexpression of AβPP and tau individually can enhance autophagy but impair mitophagy.
  • The synergistic effect of AβPP and tau is required to fully recapitulate the mitophagy failure seen in sporadic Alzheimer's disease.
  • These findings highlight a critical role for combined AβPP and tau pathology in mitochondrial dysfunction in AD.
Keywords:
Alzheimer’s diseaseamyloid-β protein precursormitochondriamitophagytau

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