The amyloid precursor protein intracellular domain (AICD) disrupts actin dynamics and mitochondrial bioenergetics

Manus W. Ward, Caoimhín G. Concannon, Jacqueline Whyte, Ciara M. Walsh, Brian Corley, Jochen H.M. Prehn

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The amyloid precursor protein (APP) is critically involved in the pathogenesis of Alzheimer's disease, and is strongly up-regulated in response to traumatic, metabolic, or toxic insults to the nervous system. The processing of APP by γ/ε-secretase activity results in the generation of the APP intracellular domain (AICD). Previously, we have shown that AICD induces the expression of genes (transgelin, α2-actin) with functional roles in actin organization and dynamics and demonstrated that the induction of AICD and its co-activator Fe65 (AICD/Fe65) resulted in a loss of organized filamentous actin structures within the cell. As mitochondrial function is thought to be reliant on ordered actin dynamics, we examined mitochondrial function in human SHEP neuroblastoma cells inducibly expressing AICD/Fe65. Confocal analysis of the mitochondrial membrane potential (Δψm) identified a significant decrease in the Δψm in the AICD50/Fe65 over-expressing cells. This was paralleled by significantly reduced ATP levels and decreased basal superoxide production. Over-expression of the proposed AICD target gene transgelin in SHEP-SF parental cells and primary neurons was sufficient to destabilize actin filaments, depolarize Δψm, and significantly alter mitochondrial disrtibution and morphology. Our data demonstrate that the induction of AICD/Fe65 or transgelin significantly alters actin dynamics and mitochondrial function in neuronal cells.

Original languageEnglish (US)
Pages (from-to)275-284
Number of pages10
JournalJournal of Neurochemistry
Volume113
Issue number1
DOIs
StatePublished - Apr 2010
Externally publishedYes

Keywords

  • APP intracellular domain
  • Alzheimer's disease
  • Mitochondrial membrane potential
  • Superoxide
  • Transgelin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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