β-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog-Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models

Biol Psychiatry. 2018 Mar 1;83(5):416-427. doi: 10.1016/j.biopsych.2017.04.011. Epub 2017 May 3.

Abstract

Background: Mitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer's disease-affected brains by yet unexplained mechanisms.

Methods: We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which presenilins control phosphatase and tensin homolog-induced kinase 1 (Pink-1) expression and transcription. In vivo approaches were carried out on various transgenic and knockout animals as well as in adeno-associated virus-infected mice. Functional readout and mitochondrial physiology (mitochondrial potential) were assessed by combined procedures including flow cytometry, live imaging analysis, and immunohistochemistry.

Results: We show that presenilins 1 and 2 trigger opposite effects on promoter transactivation, messenger RNA, and protein expression of Pink-1. This control is linked to γ-secretase activity and β-amyloid precursor protein but is independent of phosphatase and tensin homolog. We show that amyloid precursor protein intracellular domain (AICD) accounts for presenilin-dependent phenotype and upregulates Pink-1 transactivation in cells as well as in vivo in a Forkhead box O3a-dependent manner. Interestingly, the modulation of γ-secretase activity or AICD expression affects Pink-1-related control of mitophagy and mitochondrial dynamics. Finally, we show that parkin acts upstream of presenilins to control Pink-1 promoter transactivation and protein expression.

Conclusions: Overall, we delineate a molecular cascade presenilins-AICD-Forkhead box O3a linking parkin to Pink-1. Our study demonstrates AICD-mediated Pink-1-dependent control of mitochondrial physiology by presenilins. Furthermore, it unravels a parkin-Pink-1 feedback loop controlling mitochondrial physiology that could be disrupted in neurodegenerative conditions.

Keywords: 3xTgAD Mice; AICD; FOXO3a; Mitochondrial dysfunction; Mitophagy; Parkin; Pink-1; Presenilins; γ-Secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Cell Line
  • Disease Models, Animal
  • Embryo, Mammalian
  • Fibroblasts
  • Forkhead Box Protein O3 / metabolism*
  • HEK293 Cells
  • Hippocampus / metabolism*
  • Humans
  • Intracellular Space / metabolism
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Presenilins / metabolism*
  • Protein Kinases / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • Presenilins
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • Amyloid Precursor Protein Secretases