. rAAV-based brain slice culture models of Alzheimer's and Parkinson's disease inclusion pathologies. J Exp Med. 2019 Mar 4;216(3):539-555. Epub 2019 Feb 15 PubMed.


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  1. This study describes a toolkit for studying neurofibrillary inclusion and Lewy body formation in an in vivo-like murine environment. Organotypic brain slice cultures have been used to study brain cells ex vivo for more than a decade. Multiple tauopathy and AD murine brain slice culture (BSC) models have been previously reported, most of which used the established tauopathy or AD transgenic mice (Croft and Noble, 2018; Croft et al., 2017; Harwell and Coleman, 2016; Humpel, 2015; Messing et al., 2013; Mewes et al., 2012; Benediktsson et al., 2005). 

    Here, Drs. Croft and Golde describe mouse BSC models of neurofibrillary inclusion and Lewy body formation using rAAVs that express tau or α-synuclein variants in different brain cell types. They showed that overexpression of combinations of mutations leading to tau aggregation (S320F/P301L and S320F/P301L/A152T) induced robust Thio-S positive and Sarkosyl-insoluble tau aggregates in 28 days of culture. Importantly, these mutations are not directly associated with Alzheimer's disease, and accelerated tau aggregation owing to FTLD mutations would confound the elucidation of upstream pathogenic events linking Aβ deposition to tau aggregation in AD.

    Previously, human iPSC-derived neural cell cultures from AD patients have been shown to undergo accumulation of hyperphosphorylated tau proteins (Van Der Kant et al., 2019Ovchinnikov et al., 2018; Ochalek et al., 2017Raja et al., 2016; Moore et al., 2015; Muratore et al., 2014; Shi et al., 2012; Israel et al., 2012). However, as Croft et al. point out, it is difficult to obtain actual tau inclusion pathology in human iPSC-derived neural cell cultures.

    Along these lines, Croft et al. referenced our study (Choi et al., 2014). We employed human neuronal progenitor cells (RenCell VM™ originally derived from human fetal brain), infected with Lentiviral constructs expressing APP/PS1 with FAD mutations, and we grew these cells in a three-dimensional system. This led to robust Aβ and tau pathology, including not only the accumulation of hyperphosphorylated tau in dendrites and cell bodies, but also detergent-insoluble tau species with tangle-like filamentous structure, as shown by EM. Importantly, this pathology was achieved without overexpressing either wild-type or mutant tau.

    In an effort to improve our three-dimensional models, in collaboration with Dr. Cho’s lab at UNCC, we recently reported a three-dimensional human neuron-astrocyte-microglia triculture model that can recapitulate robust neurons death and inflammation in human AD brain-like environment (Park et al., 2018). To date, filamentous tau tangle-like structures have not been achieved in other human neural cell culture models.

    We strongly believe that our three-dimensional human cell culture models for AD, as well as Dr. Croft’s new rAAV BSC tau murine models employing overexpression of FTLD-associated tau mutations (and an α-synuclein mutation), should facilitate the search for novel therapeutic target for AD and related diseases.


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