Journal Article

DZNE-2020-06834

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Screening of a neuronal cell model of tau pathology for therapeutic compounds.

Pickhardt, M. (First author)DZNE* ; Tassoni, M.DZNE* ; Denner, P.DZNE* ; Kurkowsky, B.DZNE* ; Kitanovic, A.DZNE* ; Möhl, C.DZNE* ; Fava, E.DZNE* ; Mandelkow, E. (Last author)DZNE*

2019
Elsevier Science Amsterdam [u.a.]

This record in other databases:    

Please use a persistent id in citations: doi:10.1016/j.neurobiolaging.2018.11.026

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.

Keyword(s): Cell Line (MeSH) ; Drug Evaluation, Preclinical: methods (MeSH) ; Enzyme Inhibitors: pharmacology (MeSH) ; Histone Deacetylase Inhibitors (MeSH) ; Histone Deacetylases: pharmacology (MeSH) ; Humans (MeSH) ; Models, Biological (MeSH) ; Protein Aggregation, Pathological: genetics (MeSH) ; Protein Aggregation, Pathological: metabolism (MeSH) ; Signal Transduction: genetics (MeSH) ; Signal Transduction: physiology (MeSH) ; Tauopathies: drug therapy (MeSH) ; Tauopathies: genetics (MeSH) ; Tauopathies: metabolism (MeSH) ; p38 Mitogen-Activated Protein Kinases: antagonists & inhibitors (MeSH) ; tau Proteins: metabolism (MeSH) ; Enzyme Inhibitors ; Histone Deacetylase Inhibitors ; tau Proteins ; p38 Mitogen-Activated Protein Kinases ; Histone Deacetylases

---

Contributing Institute(s):

1. Structural Principles of Neurodegeneration (AG Mandelkow 1)
2. Systems Phenomics (AG Fava 1)
3. Laboratory Automation Technologies (CRFS-LAT) (LAT)
4. Image and Data Analysis (CRFS-IDAF) (IDAF)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

---

Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

---