\nThe lab has developed methods to reproduce the pathology and pathophysiology of Alzheimer\u2019s disease using 3 dimensional assemblies of human neurons, astrocytes and microglial cells which we term AstAD. The AstAD system exhibits classic markers of tau pathology including hyper-phosphorylated tau, oligomeric tau and fibrillar tau. The AstAD system also exhibits neurodegeneration, marked by loss of MAP2 signal, increased LDH release and cleaved caspase 3. This is associated with gliosis. Single cell RNAseq studies of AstAD shows rapid, striking adaptation of ribosomal transcripts in neurons and astrocytes in response to the tau-mediated stress.
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![\"\"](\"\/wolozinlab\/files\/2021\/03\/Fig-7-AstAD.jpg\")
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<\/a>\n\t\t\t<\/div><\/figure>\n\t\t<\/div>\n<\/p>\nRickner#, H.D., Jiang#, L., Hong, R., O\u2019Neill, N. K., Wolozin*, B., Cheng*, C. S., Single cell transcriptomic profiling of neurodegeneration mediated by tau propagation in a novel 3D neuron-astrocyte coculture model. Nature Med. (2021, in review) <\/font><\/p>\n Optogenetics<\/font><\/strong> Lulu Jiang, Weiwei Lin, \u2026\u2026Andrew Emili, Benjamin Wolozin, A Complex Containing HNRNPA2B1 and N6-methyladenosine Modified Transcripts Mediates Actions of Toxic Tau Oligomers. (BIORXIV\/2020\/409334)<\/font><\/p>\n Proteomics\/Emili<\/font><\/strong>
\nWe have developed an optogenetic system for inducing tau oligomerization in a temporally controlled manner, and then combined this approach with proteomics to identify proteins that preferentially bind oTau. The optogenetics approach allows us to precisely outline the steps associated with formation of tau pathology \u2013 identifying nucleocytoplasmic translocation of TIA1 and other RNA binding proteins followed by disruption of protein synthesis and of the nuclear membrane, followed by neurodegeneration.
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\nWe have teamed up with the proteomics expert, Andrew Emili, to dissect the biology of AD, FTD and ALS. We have worked with the Emili group to develop BraInMap, which uses artificial intelligence and multiplexed chromatography to elucidate native protein complexes in the brain and associated with disease. This work led to the discovery that TDP-43 works in conjunction with HNRNPH1 and DDX5 to regulate splicing of key target transcripts. This work also led to discovery of the protein::protein interaction network that drives tau biology.
\n![\"\"](\"\/wolozinlab\/files\/2021\/03\/Fig-11-BrainMap-1.jpg\")
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![\"\"](\"\/wolozinlab\/files\/2021\/03\/Fig-12-TDP43-regulation.jpg\")
<\/a>\n\t\t\t<\/div><\/figure>\n\t\t<\/div>\n<\/p>\n![\"\"](\"\/wolozinlab\/files\/2021\/03\/Fig-13-circRNA.png\")
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