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Free keywords:
Alzheimer
’
s disease, Skin cells,
γ
-secretase, Induced pluripotent stem cells,
TNFRSF1A
, Neuronal cells,
p-tau, Transcriptome, Proteasome
Abstract:
Background:
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. To investigate underlying disease
mechanisms, induced pluripotent stem cells (iPSCs) allow the generation of patient-derived neuronal cells in a dish.
Results:
In 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 consti
tutive 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.
Conclusions:
Our study demonstrates how an iPSC-based model
system could represent (i) a tool to study the
underlying molecular basis of sporad
ic AD, (ii) a platform for drug screening and toxicology studies which might unveil novel therapeutic avenues for this debilitating neuronal disorder.
