Transgenic Expression of the Amyloid-β Precursor Protein-Intracellular Domain Does Not Induce Alzheimer's Disease–Like Traits In Vivo

Luca Giliberto,Peter Davies,Christopher Michael Acker,Cristina D'Abramo,Luciano D'Adamio,Mark A Smith

doi:10.1371/journal.pone.0011609

Abstract

BackgroundRegulated intramembranous proteolysis of the amyloid-β precursor protein by the γ-secretase yields amyloid-β, which is the major component of the amyloid plaques found in Alzheimer's disease (AD), and the APP intracellular domain (AID). In vitro studies have involved AID in apoptosis and gene transcription. In vivo studies, which utilize transgenic mice expressing AID in the forebrain, only support a role for AID in apoptosis but not gene transcription.Methodology/Principal FindingsHere, we have further characterized several lines of AID transgenic mice by crossing them with human Tau-bearing mice, to determine whether over-expression of AID in the forebrain provokes AD-like pathologic features in this background. We have found no evidence that AID overexpression induces AD-like characteristics, such as activation of GSK-3β, hyperphosphorylation of Tau and formation of neurofibrillary pathology.Conclusions/SignificanceOverall, these data suggest that AID transgenic mice do not represent a model that reproduces the overt biochemical and anatomo-pathologic lesions observed in AD patients. They can still be a valuable tool to understand the role of AID in enhancing the cell sensitivity to apoptotic stimuli, whose pathways still need to be characterized.

Highlights

Alzheimer disease (AD) is characterized by the production of amyloidogenic peptides, neurofibrillary tangles (NFT) and neurodegeneration [1,2]
In Alzheimer’s disease (AD), the amyloid lesions are formed by Ab42, which derives from the Amyloid-b Precursor Protein (APP)
APP intracellular domain (AID)/hTau mice general characteristics Mice are presenting with normal growth and weaning, thrive at appropriate age

Summary

Introduction

Alzheimer disease (AD) is characterized by the production of amyloidogenic peptides, neurofibrillary tangles (NFT) and neurodegeneration [1,2]. The short AID/AICD is a biologically active intracellular peptide, which modulates cell death, gene transcription and Ca++ homeostasis [8,9,10,11,12,13,14,15,16,17,18,19]. Caspase-derived APP fragments, such as C31 [20] and Jcasp [9,21], posses in vitro toxic activities Because of these evidence, various APP-derived fragments, such as AID/AICD [10,22], C31 [23], JCasp [9], sAPPb [7] have been implicated in neurodegenerative processes. Regulated intramembranous proteolysis of the amyloid-b precursor protein by the c-secretase yields amyloidb, which is the major component of the amyloid plaques found in Alzheimer’s disease (AD), and the APP intracellular domain (AID). In vivo studies, which utilize transgenic mice expressing AID in the forebrain, only support a role for AID in apoptosis but not gene transcription

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Conclusion