Dataset Information


Misprocessing of APP and accumulation of β-Amyloid causes early alteration of pathways implicated in late-onset Alzheimer disease.

ABSTRACT: Genome-wide association studies (GWAS) have identified genes in lipid metabolism,inflammation and vesicular trafficking pathways as risk factors for late onset Alzheimer disease (LOAD). The mechanism by which they cause AD and their relationship to the amyloid cascade affected by genes causing early onset familial AD is unknown. Unproven hypotheses are that these LOAD genes modulate the amyloid cascade itself or downstream targets affected by this cascade.If so, it is likely that these genes and/or other genes in the same pathways may show alterations in their expression as an early consequence of misprocessing of amyloid precursor protein (APP) and accumulation of amyloid β-peptides (Aβ). We report that in three independent APP transgenic mouse models of AD, multiple genes in lipid and inflammation pathways show very early changes in mRNA and protein expression. Many of these changes are reversed by treatment with LXR agonists, which regulate transcription of genes in lipid/inflammation pathways, and which we have previously shown can reverse the cognitive deficits and neuropathology in Tg2756 mice. These results suggest that changes in lipid and inflammation pathways are likely to be very early consequences of APP misprocessing and Aβ accumulation in AD. Moreover, genetic variants within these pathways might affect risk for AD by modulating this early response. These pathways are likely to contain biomarkers of early disease and targets for therapies. TgCRND8 mice and wild-type littermate controls at ages 70, 80, and 150 days (n = 4 mice per cohort) were used in the study.

ORGANISM(S): Mus musculus  

SUBMITTER: David Riddell   Peter H St George-Hyslop  Naomi Visanji  Helen Warwick  Erik D Roberson  Lili-Naz Hazrati  Mahdi Ghani  Christopher Bohm  Jochen Walter  Lennart Mucke  Lindsay A Farrer  Janice Wong  William J Meilandt  Tarek A Samad  David von Schack  Badri Vadarajan  Ekaterina Rogaeva  Richard Mayeux  Suzan Aschmies  Yosuke Wakutani  Max Follettie  Shinya Tokuhiro  Fusheng Chen  Peter St George-Hyslop  Christine Sato 

PROVIDER: E-GEOD-31372 | ArrayExpress | 2014-08-12



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