Abstract
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 effects of the amyloid-binding tetra (ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, on tau. BTA-EG4 significantly 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 findings 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 effects of BTA-EG4 that are likely related to the ability of this agent to inactivate GSK-3. Our findings support the further exploration of BTA-EG4 as a candidate therapeutic for Alzheimer’s disease.
Highlights
Alzheimer’s disease (AD) is characterised pathologically by the presence, predominantly in the hippocampus, neocortex and interconnecting regions, of β-amyloid (Aβ)-containing extracellular plaques and intracellular neurofibrillary tangles comprising hyperphosphorylated and cleaved forms of tau[1,2,3]
We have recently shown that some prominent molecular phenotypes of neurodegeneration exhibited by 3xTg-AD mice are recapitulated in organotypic brain slice cultures produced from these mice at postnatal day 8–9 and subsequently maintained in culture for up to 28 days in vitro (DIV)16. 3xTg-AD brain slice cultures rapidly show increased production of Aβ-42, an increased Aβ-42/Aβ-40 ratio, tau phosphorylation at AD-relevant epitopes, such as Ser[202] and Ser396/404, and tau mislocalisation and altered release when compared to control WT slice cultures[16]
We found that treating 3xTg-AD slice cultures with the GSK-3 inhibitor lithium chloride (LiCl), or the microtubule-binding agent NAPVSIPQ, reduces tau phosphorylation at sites implicated in AD, recapitulating previously reported in vivo findings in aged 3xTg-AD mice[17,18,19]
Summary
Alzheimer’s disease (AD) is characterised pathologically by the presence, predominantly in the hippocampus, neocortex and interconnecting regions, of β-amyloid (Aβ)-containing extracellular plaques and intracellular neurofibrillary tangles comprising hyperphosphorylated and cleaved forms of tau[1,2,3]. 3xTg-AD brain slice cultures rapidly show increased production of Aβ-42, an increased Aβ-42/Aβ-40 ratio, tau phosphorylation at AD-relevant epitopes, such as Ser[202] and Ser396/404, and tau mislocalisation and altered release when compared to control WT slice cultures[16]. These molecular phenotypes are accelerated in culture compared to in vivo. We present novel data showing tau-directed effects of BTA-EG4 that are associated with BTA-EG4-mediated inhibition of GSK-3 These data highlight the utility of organotypic brain slice culture models for accelerated drug screening and support further exploration of BTA-EG4 and related derivatives for the treatment of AD and other tauopathies
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