Transcription profiling of human SHEP-SF cells expressing AICD and Fe65
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Thorsten Mueller
PROVIDER: E-GEOD-4097 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Modulation of gene expression and cytoskeletal dynamics by the amyloid precursor protein intracellular domain (AICD).
Müller Thorsten T Concannon Caoimhin G CG Ward Manus W MW Walsh Ciara M CM Tirniceriu Anca L AL Tribl Florian F Kögel Donat D Prehn Jochen H M JH Egensperger Rupert R
Molecular biology of the cell 20061108 1
Amyloidogenic processing of the amyloid precursor protein (APP) results in the generation of beta-amyloid, the main constituent of Alzheimer plaques, and the APP intracellular domain (AICD). Recently, it has been demonstrated that AICD has transactivation potential; however, the targets of AICD-dependent gene regulation and hence the physiological role of AICD remain largely unknown. We analyzed transcriptome changes during AICD-dependent gene regulation by using a human neural cell culture syst ...[more]
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Project description:Ortega2013 - Interplay between secretases
determines biphasic amyloid-beta level
This model is described in the article:
Interplay between ?-, ?-,
and ?-secretases determines biphasic amyloid-? protein level in
the presence of a ?-secretase inhibitor.
Ortega F, Stott J, Visser SA,
Bendtsen C.
J. Biol. Chem. 2013 Jan; 288(2):
785-792
Abstract:
Amyloid-? (A?) is produced by the consecutive cleavage of
amyloid precursor protein (APP) first by ?-secretase,
generating C99, and then by ?-secretase. APP is also cleaved by
?-secretase. It is hypothesized that reducing the production of
A? in the brain may slow the progression of Alzheimer disease.
Therefore, different ?-secretase inhibitors have been developed
to reduce A? production. Paradoxically, it has been shown that
low to moderate inhibitor concentrations cause a rise in A?
production in different cell lines, in different animal models,
and also in humans. A mechanistic understanding of the A? rise
remains elusive. Here, a minimal mathematical model has been
developed that quantitatively describes the A? dynamics in cell
lines that exhibit the rise as well as in cell lines that do
not. The model includes steps of APP processing through both
the so-called amyloidogenic pathway and the so-called
non-amyloidogenic pathway. It is shown that the cross-talk
between these two pathways accounts for the increase in A?
production in response to inhibitor, i.e. an increase in C99
will inhibit the non-amyloidogenic pathway, redirecting APP to
be cleaved by ?-secretase, leading to an additional increase in
C99 that overcomes the loss in ?-secretase activity. With a
minor extension, the model also describes plasma A? profiles
observed in humans upon dosing with a ?-secretase inhibitor. In
conclusion, this mechanistic model rationalizes a series of
experimental results that spans from in vitro to in vivo and to
humans. This has important implications for the development of
drugs targeting A? production in Alzheimer disease.
This model is hosted on
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and identified by:
BIOMD0000000556.
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To the extent possible under law, all copyright and related or
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2024-09-02 | BIOMD0000000556 | BioModels
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Project description:In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the α-secretase ADAM10 prevented amyloid plaque formation and alleviated cognitive deficits. Furthermore, there was a positive influence of ADAM10 over-expression on neurotransmitter-specific formation of synapses and on synaptic plasticity. To assess the influence of ADAM10 on the gene expression profile in the brain we performed microarray analysis using RNA isolated from brains of five month old mice over-expressing either the α-secretase ADAM10 or a dominant-negative mutant (dn) of this enzyme. As compared to non-transgenic wild-type mice, 355 genes were found to be differentially expressed in ADAM10 transgenic mice and 143 genes in dnADAM10 mice. A higher number of genes was found to be differentially regulated in double-transgenic mouse strains additionally expressing the human APP V717I mutant (APP[V717I]). Thus, α-secretase cleavage of over-expressed APP[V717I] alters CNS gene expression additionally. Keywords: genetic modification
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