2014 Annual Report: 10 Years of Leading Research

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Generation of iPS Cells and Neurons from Skin Fibroblasts from Subjects with Familial and Sporadic AD

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Molecular, Biochemical and Functional Characterization of the AD iPS Cell Lines

Identification of Transcriptional and Proteomic Profiles of Familial and Sporadic AD iPS Cells

Genetic approaches have provided major insights into the molecular pathogenesis of AD. However, only about 3 percent of all of AD is due to genetic mutations in either amyloid precursor protein (APP) or presenilin 1 or 2 (PSEN1, PSEN2). A particular promise for the recent success in differentiating skin fibroblasts into phenotypes of brain neurons provides an unprecedented and unequaled cell system for exploring AD pathogenesis in both familial and sporadic AD. We propose to generate a human in vitro model using iPS cells, in which the genetic and developmental aspects of familial and sporadic AD can be studied more accurately and therapeutic targets can be identified for subsequent drug discovery. The cell-type specificity of key AD risk molecules (e.g., apoE and astrocytes) dictates that the complete modeling of the AD brain in culture will require the generation of neurons and glia and the study of these cells in mixed cultures. Ultimately, we will transplant these neurons into mouse brains in order to study their molecular and physiological properties in vivo.