Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the cytoplasmic domain of the Alzheimer's β-amyloid precursor protein (APP)

Meir H. Scheinfeld, Roberta Roncarati, Pasquale Vito, Peter A. Lopez, Mona Abdallah, Luciano D'Adamio

Research output: Contribution to journalArticle

142 Scopus citations

Abstract

The familial Alzheimer's disease gene product amyloid βprecursor protein (APP) is sequentially processed by β- and γ-secretases to generate the Aβ peptide. The biochemical pathway leading to Aβ formation has been extensively studied since extracellular aggregates of Aβ peptides are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of APP processing is unknown. Cleavage of APP by γ-secretase releases, together with Aβ, a COOH-terminal APP intracellular domain, termed AID. This peptide has recently been identified in brain tissue of normal control and patients with sporadic Alzheimer's disease. We have previously shown that AID acts as a positive regulator of apoptosis. Nevertheless, the molecular mechanism by which AID regulates this process remains unknown. Hoping to gain clues about the function of APP, we used the yeast two-hybrid system to identify interaction between the AID region of APP and JNK-interacting protein-1 (JIP1). This molecular interaction is confirmed in vitro, in vivo by fluorescence resonance energy transfer (FRET), and in mouse brain lysates. These data provide a link between APP and its processing by γ-secretase, and stress kinase signaling pathways. These pathways are known regulators of apoptosis and may be involved in the pathogenesis of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)3767-3775
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number5
DOIs
StatePublished - Feb 1 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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