Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 216, Issue 3, Pages 539-555Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20182184
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Funding
- Stop Alzheimer's Now and Marjorie Thomas Fund
- National Institutes of Health [U01AG046139, R01AG018454, P50AG047266, 1S10OD020026]
- Florida Department of Health [7AZ25]
- BrightFocus Foundation [A2018149F]
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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 a-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.
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