rAAV-based brain slice culture models of Alzheimer’s and Parkinson’s disease inclusion pathologies

Cara L. Croft, Pedro E. Cruz, Daniel H. Ryu, Carolina Ceballos-Diaz, Kevin H. Strang, Brittany M. Woody, Wen Lang Lin, Michael Deture, Edgardo Rodríguez-Lebrón, Dennis W. Dickson, Paramita Chakrabarty, Yona Levites, Benoit I. Giasson, Todd E. Golde

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

It has been challenging to produce ex vivo models of the inclusion pathologies that are hallmark pathologies of many neurodegenerative diseases. Using three-dimensional mouse brain slice cultures (BSCs), we have developed a paradigm that rapidly and robustly recapitulates mature neurofibrillary inclusion and Lewy body formation found in Alzheimer’s and Parkinson’s disease, respectively. This was achieved by transducing the BSCs with recombinant adeno-associated viruses (rAAVs) that express α-synuclein or variants of tau. Notably, the tauopathy BSC model enables screening of small molecule therapeutics and tracking of neurodegeneration. More generally, the rAAV BSC “toolkit” enables efficient transduction and transgene expression from neurons, microglia, astrocytes, and oligodendrocytes, alone or in combination, with transgene expression lasting for many months. These rAAV-based BSC models provide a cost-effective and facile alternative to in vivo studies, and in the future can become a widely adopted methodology to explore physiological and pathological mechanisms related to brain function and dysfunction.

Original languageEnglish (US)
Pages (from-to)539-555
Number of pages17
JournalJournal of Experimental Medicine
Volume216
Issue number3
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Croft, C. L., Cruz, P. E., Ryu, D. H., Ceballos-Diaz, C., Strang, K. H., Woody, B. M., Lin, W. L., Deture, M., Rodríguez-Lebrón, E., Dickson, D. W., Chakrabarty, P., Levites, Y., Giasson, B. I., & Golde, T. E. (2019). rAAV-based brain slice culture models of Alzheimer’s and Parkinson’s disease inclusion pathologies. Journal of Experimental Medicine, 216(3), 539-555. https://doi.org/10.1084/jem.20182184