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@ARTICLE{Pickhardt:140512,
author = {Pickhardt, Marcus and Tassoni, Michele and Denner, Philip
and Kurkowsky, Birgit and Kitanovic, Ana and Möhl,
Christoph and Fava, Eugenio and Mandelkow, Eckhard},
title = {{S}creening of a neuronal cell model of tau pathology for
therapeutic compounds.},
journal = {Neurobiology of aging},
volume = {76},
issn = {0197-4580},
address = {Amsterdam [u.a.]},
publisher = {Elsevier Science},
reportid = {DZNE-2020-06834},
pages = {24-34},
year = {2019},
abstract = {We have developed a cell-based phenotypic automated
high-content screening approach for N2a cells expressing the
pro-aggregant repeat domain of tau protein (tauRDΔK), which
allows analysis of a chemogenomic library of 1649 compounds
for their effect on the inhibition or stimulation of
intracellular tau aggregation. We identified several
inhibitors and stimulators of aggregation and achieved a
screening reproducibility $>85\%$ for all data. We
identified 18 potential inhibitors (= $1.1\%$ of the
library) and 10 stimulators (= $0.6\%$ of the library) of
tau aggregation in this cell model of tau pathology. The
results provide insights into the regulation of cellular tau
aggregation and the pathways involved in this process (e.g.,
involving signaling via p38 mitogen-activated protein
kinase, histone deacetylases, vascular endothelial growth
factor, rho/ROCK). For example, inhibitors of protein
kinases (e.g., p38) can reduce tau aggregation, whereas
inhibitors of deacetylases (histone deacetylases) can
enhance aggregation. These observations are compatible with
reports that phosphorylated or acetylated tau promotes
pathology.},
keywords = {Cell Line / Drug Evaluation, Preclinical: methods / Enzyme
Inhibitors: pharmacology / Histone Deacetylase Inhibitors /
Histone Deacetylases: pharmacology / Humans / Models,
Biological / Protein Aggregation, Pathological: genetics /
Protein Aggregation, Pathological: metabolism / Signal
Transduction: genetics / Signal Transduction: physiology /
Tauopathies: drug therapy / Tauopathies: genetics /
Tauopathies: metabolism / p38 Mitogen-Activated Protein
Kinases: antagonists $\&$ inhibitors / tau Proteins:
metabolism / Enzyme Inhibitors (NLM Chemicals) / Histone
Deacetylase Inhibitors (NLM Chemicals) / tau Proteins (NLM
Chemicals) / p38 Mitogen-Activated Protein Kinases (NLM
Chemicals) / Histone Deacetylases (NLM Chemicals)},
cin = {AG Mandelkow 1 / AG Fava 1 / LAT / IDAF},
ddc = {610},
cid = {I:(DE-2719)1013014 / I:(DE-2719)1013016 /
I:(DE-2719)1040190 / I:(DE-2719)1040200},
pnm = {342 - Disease Mechanisms and Model Systems (POF3-342)},
pid = {G:(DE-HGF)POF3-342},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30640040},
doi = {10.1016/j.neurobiolaging.2018.11.026},
url = {https://pub.dzne.de/record/140512},
}