P1–103: The amyloid precursor protein regulates brain lipid homeostasis

Background: The amyloid hypothesis continues to be a valid basis for potential therapeutic approaches in Alzheimer's disease (AD), but the slow progress of amyloid-centric therapies highlights our poor understanding of the basic biology of the amyloid precursor protein (APP) and its bioactive fragments, including Abeta. Clearly, a better theoretical understanding of its function in the brain is necessary before we can either dismiss or improve amyloid-centric therapies. To that end, we have proposed a hypothesis of neurodegeneration in which cholesterol dysregulation is an early pathogenic trigger in most cases of late-onset AD, and Abeta generation occurs as part of an adaptive response to cholesterol-associated cellular stress. To test that hypothesis, we have carried out an integrative systems study combining in vivo, in vitro and in silico models to identify APP-dependent mechanisms of lipid regulation in the brain and assess their role in AD pathogenesis. Methods: Cerebella and cortex from 3-week-old mice of wild type and APP ko genotypes were processed for RNA extraction and gene expression profiling on an Agilent mouse v2 microarray platform, and analyzed using Ingenuity Pathway Analysis software. Transcriptome- To-Metabolome™ (TTM™) Biosimulations of 20 primary and secondary metabolic pathways, including cholesterol and sphingolipids, were carried out. Flux and metabolite pathway maps were generated with NodeXL and integrated gene expression differences. Results: Gene expression analysis revealed the presence of genes involved in the regulation of sphingolipid and cholesterol metabolism that are differentially expressed in the absence of APP, both in cortex and cerebellum of APP ko mice. Furthermore, TTM™ Biosimulations confirm the presence of widespread abnormal cholesterol and sphingolipid metabolic pathways. Pathway maps revealed that flux changes do not always follow gene expression changes. Conclusions: Our results confirm at multiple levels that APP contributes to regulation of cholesterol and sphingolipid pathways in the mouse brain. Work is currently under way to establish causal links amongst differentially expressed genes associated to these pathways. Generation of such a “hierarchical pathogenic map” developing as a consequence of APP loss will inform the identification of novel therapeutic targets.