Abstract
BackgroundAlzheimer’s disease (AD) is a complex, irreversible neurodegenerative disorder. At present there are neither reliable markers to diagnose AD at an early stage nor therapy. To investigate underlying disease mechanisms, induced pluripotent stem cells (iPSCs) allow the generation of patient-derived neuronal cells in a dish.ResultsIn this study, employing iPS technology, we derived and characterized iPSCs from dermal fibroblasts of an 82-year-old female patient affected by sporadic AD. The AD-iPSCs were differentiated into neuronal cells, in order to generate disease-specific protein association networks modeling the molecular pathology on the transcriptome level of AD, to analyse the reflection of the disease phenotype in gene expression in AD-iPS neuronal cells, in particular in the ubiquitin-proteasome system (UPS), and to address expression of typical AD proteins.We detected the expression of p-tau and GSK3B, a physiological kinase of tau, in neuronal cells derived from AD-iPSCs. Treatment of neuronal cells differentiated from AD-iPSCs with an inhibitor of γ-secretase resulted in the down-regulation of p-tau. Transcriptome analysis of AD-iPS derived neuronal cells revealed significant changes in the expression of genes associated with AD and with the constitutive as well as the inducible subunits of the proteasome complex. The neuronal cells expressed numerous genes associated with sub-regions within the brain thus suggesting the usefulness of our in-vitro model. Moreover, an AD-related protein interaction network composed of APP and GSK3B among others could be generated using neuronal cells differentiated from two AD-iPS cell lines.ConclusionsOur study demonstrates how an iPSC-based model system could represent (i) a tool to study the underlying molecular basis of sporadic AD, (ii) a platform for drug screening and toxicology studies which might unveil novel therapeutic avenues for this debilitating neuronal disorder.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1262-5) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) is a complex, irreversible neurodegenerative disorder
We demonstrated a down-regulation of p-tau proteins in AD neuronal cells with an inhibitor of γ-secretase
Generation and characterization of sporadic AD-induced pluripotent stem cells (iPSCs) Dermal fibroblasts were isolated from an 82-year-old woman diagnosed with final stage AD
Summary
Alzheimer’s disease (AD) is a complex, irreversible neurodegenerative disorder. At present there are neither reliable markers to diagnose AD at an early stage nor therapy. The familial form of AD is rare, affecting less than five percent of AD patients and has been associated with mutations of Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and Amyloid Precursor Protein (APP) [3,4] These mutations result in incorrect cleavage of the protein, producing a deposited protein of amyloid-β (Aβ) that is more likely to form plaques [1,5]. In post-mortem examination of patients with AD, massive accumulation of two types of amyloid fibril senile plaques (Aβ40, Aβ42) and hyperphosphorylated tau forming paired helical filaments could be detected [6,7]. Both types of amyloid fibrils are mainly created enzymatically by β- and γ-secretase activity from the APP [8]
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