Screening of a neuronal cell model of tau pathology for therapeutic compounds.

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.

journal_name

Neurobiol Aging

journal_title

Neurobiology of aging

authors

Pickhardt M,Tassoni M,Denner P,Kurkowsky B,Kitanovic A,Möhl C,Fava E,Mandelkow E

doi

10.1016/j.neurobiolaging.2018.11.026

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

24-34

eissn

0197-4580

issn

1558-1497

pii

S0197-4580(18)30435-4

journal_volume

76

pub_type

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