The phosphatidylinositol 3-kinase inhibitor wortmannin alters the metabolism of the Alzheimer's amyloid precursor protein

Suzana S. Petanceska, Sam Gandy

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

One of the hallmarks of Alzheimer's disease is the accumulation of senile plaques in brain, extracellular lesions comprised mostly of aggregates of the amyloid β-peptide (Aβ). Aβ is proteolytically derived from the Alzheimer's amyloid precursor protein (APP). The generation of Aβ and nonamyloidogenic derivatives of APP involves utilization of alternative processing pathways and multiple subcellular compartments. To improve our understanding of the regulation of APP processing, we investigated the effects of wortmannin, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, on APP processing. PI3-kinases form a multifaceted family of enzymes that represent converging points for multiple signal transduction pathways and also act as key regulators of vesicular trafficking. In N2a neuroblastoma cells expressing either wild-type APP or the 'Swedish' familial Alzheimer's disease-associated mutant variant of APP, wortmannin treatment resulted in decreased release of both Aβ and soluble APP(α). In parallel, full-length APP and both processed derivatives accumulated inside the cells. These effects were not present at nanomolar concentrations of wortmannin, but only at micromolar concentrations, implying the possible involvement of a recently described trans-Golgi network (TGN)-associated PI3-kinase that is resistant to nanomolar concentrations of the inhibitor, but sensitive to micromolar concentrations. All effects were reversible when the drug was removed from the cell culture medium. Given the suspected site of action of this novel PI3-kinase activity at the TGN, it is tempting to speculate that the unexpected increase in the levels of both intracellular soluble APP(α) and intracellular Aβ might be due to wortmannin-induced covesiculation of APP together with its respective secretase enzymes within the TGN, leading to the execution of α-, β-, and γ-secretase reactions.

Original languageEnglish
Pages (from-to)2316-2320
Number of pages5
JournalJournal of Neurochemistry
Volume73
Issue number6
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Amyloid β-peptide
  • Soluble amyloid precursor protein-α
  • Trans-Golgi network
  • Vesicle trafficking
  • α-, β-, and γ-secretase

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