APP and its intracellular domain modulate Alzheimers disease risk gene networks in transgenic APPsw and PSEN1M146I porcine models

Abstract

Alzheimers disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia. The disease has a substantial genetic component comprising both highly penetrant familial mutations (APP, PSEN1, and PSEN2) and sporadic cases with complex genetic etiology. Mutations in APP and PSEN1/2 alter the proteolytic processing of APP to its metabolites, including A{beta} and APP Intracellular Domain (AICD). In this study, we use transgenic porcine models carrying the human APPsw and PSEN1M146I transgenes to demonstrate the pathobiological relevance of transcriptional regulation facilitated by APP and its AICD domain. Through molecular characterization of hippocampal tissue, we describe the differential expression of gene sets that cluster in molecular pathways with translational relevance to AD. We further identify phosphorylated and unphosphorylated AICD in differential complexes with proteins implicated in signal transduction and transcriptional regulation. Integrative genomic analysis of transcriptional changes in somatic cell cultures derived from pigs treated with {gamma}-secretase inhibitor demonstrates the importance of {gamma}-secretase APP processing in transcriptional regulation. Our data supports a model in which APP and, in particular, its AICD domain, modulates gene networks associated with AD pathobiology through interaction with signaling proteins. One Sentence SummaryUtilizing transgenic porcine models, our study reveals that Alzheimers disease-related mutations affect neuronal gene expression and highlights the role of the AICD domain of APP in modulating gene networks associated with Alzheimers pathobiology.