Croft CL, Cruz PE, Ryu DH, Ceballos-Diaz C, Strang KH, Woody BM, Lin WL, Deture M, Rodríguez-Lebrón E, Dickson DW, Chakrabarty P, Levites Y, Giasson BI, Golde TE. 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., 2019; Ovchinnikov et al., 2018; Ochalek et al., 2017; Raja 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.

    References:

    Croft CL, Noble W. Preparation of organotypic brain slice cultures for the study of Alzheimer's disease. F1000Res. 2018;7:592. Epub 2018 May 15 PubMed.

    Croft CL, Wade MA, Kurbatskaya K, Mastrandreas P, Hughes MM, Phillips EC, Pooler AM, Perkinton MS, Hanger DP, Noble W. Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures. Cell Death Dis. 2017 Mar 16;8(3):e2671. PubMed.

    Harwell CS, Coleman MP. Synaptophysin depletion and intraneuronal Aβ in organotypic hippocampal slice cultures from huAPP transgenic mice. Mol Neurodegener. 2016 Jun 10;11(1):44. PubMed.

    Humpel C. Organotypic vibrosections from whole brain adult Alzheimer mice (overexpressing amyloid-precursor-protein with the Swedish-Dutch-Iowa mutations) as a model to study clearance of beta-amyloid plaques. Front Aging Neurosci. 2015;7:47. Epub 2015 Apr 9 PubMed.

    Messing L, Decker JM, Joseph M, Mandelkow E, Mandelkow EM. Cascade of tau toxicity in inducible hippocampal brain slices and prevention by aggregation inhibitors. Neurobiol Aging. 2013 May;34(5):1343-54. PubMed.

    Mewes A, Franke H, Singer D. Organotypic brain slice cultures of adult transgenic P301S mice--a model for tauopathy studies. PLoS One. 2012;7(9):e45017. PubMed.

    Benediktsson AM, Schachtele SJ, Green SH, Dailey ME. Ballistic labeling and dynamic imaging of astrocytes in organotypic hippocampal slice cultures. J Neurosci Methods. 2005 Jan 30;141(1):41-53. PubMed.

    van der Kant R, Langness VF, Herrera CM, Williams DA, Fong LK, Leestemaker Y, Steenvoorden E, Rynearson KD, Brouwers JF, Helms JB, Ovaa H, Giera M, Wagner SL, Bang AG, Goldstein LS. Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons. Cell Stem Cell. 2019 Mar 7;24(3):363-375.e9. Epub 2019 Jan 24 PubMed.

    Ovchinnikov DA, Korn O, Virshup I, Wells CA, Wolvetang EJ. The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons. Stem Cell Reports. 2018 Jul 10;11(1):32-42. Epub 2018 May 31 PubMed.

    Ochalek A, Mihalik B, Avci HX, Chandrasekaran A, Téglási A, Bock I, Giudice ML, Táncos Z, Molnár K, László L, Nielsen JE, Holst B, Freude K, Hyttel P, Kobolák J, Dinnyés A. Neurons derived from sporadic Alzheimer's disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res Ther. 2017 Dec 1;9(1):90. PubMed.

    Raja WK, Mungenast AE, Lin YT, Ko T, Abdurrob F, Seo J, Tsai LH. Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes. PLoS One. 2016;11(9):e0161969. Epub 2016 Sep 13 PubMed.

    Moore S, Evans LD, Andersson T, Portelius E, Smith J, Dias TB, Saurat N, McGlade A, Kirwan P, Blennow K, Hardy J, Zetterberg H, Livesey FJ. APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015 May 5;11(5):689-96. Epub 2015 Apr 23 PubMed.

    Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LN, Walsh DM, Selkoe DJ, Young-Pearse TL. The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet. 2014 Jul 1;23(13):3523-36. Epub 2014 Feb 12 PubMed.

    Shi Y, Kirwan P, Smith J, Maclean G, Orkin SH, Livesey FJ. A human stem cell model of early Alzheimer's disease pathology in Down syndrome. Sci Transl Med. 2012 Mar 7;4(124):124ra29. PubMed.

    Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature. 2012 Jan 25;482(7384):216-20. PubMed.

    Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D'Avanzo C, Chen H, Hooli B, Asselin C, Muffat J, Klee JB, Zhang C, Wainger BJ, Peitz M, Kovacs DM, Woolf CJ, Wagner SL, Tanzi RE, Kim DY. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature. 2014 Nov 13;515(7526):274-8. Epub 2014 Oct 12 PubMed.

    Park J, Wetzel I, Marriott I, Dréau D, D'Avanzo C, Kim DY, Tanzi RE, Cho H. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nat Neurosci. 2018 Jul;21(7):941-951. Epub 2018 Jun 27 PubMed.

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