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P3‐054: The amyloid‐binding agent bta‐eg 4 reduces pathological tau species in a novel organotypic 3xTg‐AD brain slice culture model that recapitulates key in vivo degenerative phenotypes
Author(s) -
Croft Cara L.,
Hanger Diane P.,
Noble Wendy
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.921
Subject(s) - in vivo , amyloid (mycology) , neuroscience , pharmacology , slice preparation , genetically modified mouse , chemistry , microbiology and biotechnology , medicine , biology , biochemistry , pathology , in vitro , transgene , genetics , gene
Background:The progressive development of amyloid and tau deposits, synaptic dysfunction and cognitive decline are well characterised in 3xTg-AD mice. 3xTg-AD mice thus provide an excellent model for testing the potential benefit of new disease-modifying treatments. Organotypic brain slice culture models provide an alternative to early stage in vivo testing since they recapitulate key disease features, and provide a higher throughput platform for drug screening. Here, we describe a novel organotypic 3xTg-AD brain slice culture model, and highlight its potential for researching the effects of disease-modifying agents such as the amyloid-binding tetra (ethylene glycol) derivative of benzothiazole aniline, BTAEG4. Methods: Organotypic brain slice cultures were prepared from neonatal 3xTg-AD and WT mice and cultured for several weeks. Slices were characterised for changes in total and phosphorylated tau and APP processing, with respect to aged mice. Slice cultures were treated with disease-modifying agents such as BTA-EG4 and the effects on abnormal tau species and APP processing were determined. Results:Organotypic brain slice cultures from 3xTgAD mice show elevated tau phosphorylation and the presence of high molecular weight tau species soon after culture, in comparison to slice cultures from WT mice. The novel amyloid-binding agent BTA-EG4, previously reported to reduce levels of beta-amyloid (Ab), increase dendritic spine density and ameliorate cognitive decline in mouse models of AD, was found here to also reduce the presence of abnormal tau species and other neurodegenerative features in 3xTg-AD brain slice cultures. Conclusions:We have successfully established a method to produce and maintain brain slices from 3xTg-AD mice in culture long-term. Our observations of rapid development of tau pathology in 3xTg-AD brain slices highlights the potential of this model as a more rapid and reliable in vitro method for drug screening prior to in vivo testing. Indeed, we demonstrate here novel tau-directed effects of BTA-EG4. The precise mode of action of this drug is currently being explored. Our findings support the further exploration of BTA-EG4 as a candidate therapeutic for Alzheimer’s disease.