Inhibition of glycogen synthase kinase-3 by BTA-EG4 reduces tau abnormalities in an organotypic brain slice culture model of Alzheimer’s disease

TY - JOUR

T1 - Inhibition of glycogen synthase kinase-3 by BTA-EG4 reduces tau abnormalities in an organotypic brain slice culture model of Alzheimer’s disease

AU - Croft, Cara Louise

AU - Kurbatskaya, Ksenia

AU - Hanger, Diane Pamela

AU - Noble, Wendy Jane

PY - 2017/8/7

Y1 - 2017/8/7

N2 - Organotypic brain slice culture models provide an alternative to early stage in vivo studies as an integrated tissue system that can recapitulate key disease features, thereby providing an excellent platform for drug screening. We recently described a novel organotypic 3xTg-AD mouse brain slice culture model with key Alzheimer’s disease-like changes. We now highlight the potential of this model for testing disease-modifying agents and show that results obtained following in vivo treatment are replicated in brain slice cultures from 3xTg-AD mice. Moreover, we describe novel efects of the amyloid-binding tetra (ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, on tau. BTA-EG4 signifcantly reduced tau phosphorylation in the absence of any changes in the amounts of amyloid precursor protein, amyloid-β or synaptic proteins. The reduction in tau phosphorylation was associated with inactivation of the Alzheimer’s disease-relevant major tau kinase, GSK-3. These fndings highlight the utility of 3xTg-AD brain slice cultures as a rapid and reliable in vitro method for drug screening prior to in vivo testing. Furthermore, we demonstrate novel tau-directed efects of BTA-EG4 that are likely related to the ability of this agent to inactivate GSK-3. Our fndings support the further exploration of BTA-EG4 as a candidate therapeutic for Alzheimer’s disease.

AB - Organotypic brain slice culture models provide an alternative to early stage in vivo studies as an integrated tissue system that can recapitulate key disease features, thereby providing an excellent platform for drug screening. We recently described a novel organotypic 3xTg-AD mouse brain slice culture model with key Alzheimer’s disease-like changes. We now highlight the potential of this model for testing disease-modifying agents and show that results obtained following in vivo treatment are replicated in brain slice cultures from 3xTg-AD mice. Moreover, we describe novel efects of the amyloid-binding tetra (ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, on tau. BTA-EG4 signifcantly reduced tau phosphorylation in the absence of any changes in the amounts of amyloid precursor protein, amyloid-β or synaptic proteins. The reduction in tau phosphorylation was associated with inactivation of the Alzheimer’s disease-relevant major tau kinase, GSK-3. These fndings highlight the utility of 3xTg-AD brain slice cultures as a rapid and reliable in vitro method for drug screening prior to in vivo testing. Furthermore, we demonstrate novel tau-directed efects of BTA-EG4 that are likely related to the ability of this agent to inactivate GSK-3. Our fndings support the further exploration of BTA-EG4 as a candidate therapeutic for Alzheimer’s disease.

KW - Alzheimer's disease (AD)

KW - tau

KW - ORGANOTYPIC SLICE CULTURES

KW - GSK3

UR - http://www.scopus.com/inward/record.url?scp=85026904731&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-07906-1

DO - 10.1038/s41598-017-07906-1

M3 - Article

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

M1 - 7434

ER -