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

doi:10.1074/jbc.m108357200

Abstract

The familial Alzheimer's disease gene product amyloid beta precursor protein (APP) is sequentially processed by beta- and gamma-secretases to generate the Abeta peptide. The biochemical pathway leading to Abeta formation has been extensively studied since extracellular aggregates of Abeta 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 gamma-secretase releases, together with Abeta, 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 gamma-secretase, and stress kinase signaling pathways. These pathways are known regulators of apoptosis and may be involved in the pathogenesis of Alzheimer's disease.

Highlights

The familial Alzheimer’s disease gene product amyloid ␤ precursor protein (APP) is sequentially processed by ␤- and ␥-secretases to generate the A␤ peptide
APP processing has become firmly associated with the pathogenesis of AD with the identification of missense mutations in three genes associated with familial forms of AD (FAD)
In this study we have demonstrated the interaction between APP and JNK-interacting protein-1 (JIP1) in vitro, in vivo, in living cells and in adult mouse brain lysates

Summary

Introduction

The familial Alzheimer’s disease gene product amyloid ␤ precursor protein (APP) is sequentially processed by ␤- and ␥-secretases to generate the A␤ peptide. Cleavage of APP by ␥-secretase releases, together with A␤, 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. 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 ␥-secretase, and stress kinase signaling pathways These pathways are known regulators of apoptosis and may be involved in the pathogenesis of Alzheimer’s disease. We describe JIP1 ( known as IB1) as a new binding partner of the APP intracellular domain

Methods

Results

Conclusion