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

Document Type

Article

Publication Date

2013

JAX Source

BMC Genomics 2013 Nov 25; 14:831.

Volume

14

First Page

831

Last Page

831

ISSN

1471-2164

PMID

24274089

Abstract

BACKGROUND: Alzheimer'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.

RESULTS: Our 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.

CONCLUSION: A 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.

BMC Genomics 2013 Nov 25; 14:831.

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