Clustering of transcriptional profiles identifies changes to insulin signaling as an early event in a mouse model of Alzheimer’s disease

BMC Genomics

Research Article

Gregory W Carter¹  Ileana Soto¹  Harriet M Jackson¹  Leah C Graham²  Gareth R Howell² 

[1] The Jackson Laboratory, 600 Main Street, 04609, Bar Harbor, Maine, USA;The Jackson Laboratory, 600 Main Street, 04609, Bar Harbor, Maine, USA;School of Medicine, Tufts University, Boston, USA;

关键词: Singular Value Decomposition;    Amyloid Precursor Protein;    Neurofibrillary Tangle;    Differentially Express;    Transcriptional Profile;   

DOI  :  10.1186/1471-2164-14-831

 received in 2013-09-06, accepted in 2013-11-14,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundAlzheimer’s disease affects more than 35 million people worldwide but there is no known cure. Age is the strongest risk factor for Alzheimer’s disease but it is not clear how age-related changes impact the disease. Here, we used a mouse model of Alzheimer’s disease to identify age-specific changes that occur prior to and at the onset of traditional Alzheimer-related phenotypes including amyloid plaque formation. To identify these early events we used transcriptional profiling of mouse brains combined with computational approaches including singular value decomposition and hierarchical clustering.ResultsOur study identifies three key events in early stages of Alzheimer’s disease. First, the most important drivers of Alzheimer’s disease onset in these mice are age-specific changes. These include perturbations of the ribosome and oxidative phosphorylation pathways. Second, the earliest detectable disease-specific changes occur to genes commonly associated with the hypothalamic-adrenal-pituitary (HPA) axis. These include the down-regulation of genes relating to metabolism, depression and appetite. Finally, insulin signaling, in particular the down-regulation of the insulin receptor substrate 4 (Irs4) gene, may be an important event in the transition from age-related changes to Alzheimer’s disease specific-changes.ConclusionA combination of transcriptional profiling combined with computational analyses has uncovered novel features relevant to Alzheimer’s disease in a widely used mouse model and offers avenues for further exploration into early stages of AD.

【 授权许可】

Unknown   
© Jackson et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.