Quantitative propagation of assembled human Tau from Alzheimer's disease brain in microfluidic neuronal cultures

• Published in: The Journal of biological chemistry Vol. 295; no. 37; pp. 13079 - 13093
• Main Authors: Katsikoudi, Antigoni, Ficulle, Elena, Cavallini, Annalisa, Sharman, Gary, Guyot, Amelie, Zagnoni, Michele, Eastwood, Brian J., Hutton, Michael, Bose, Suchira
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-09-2020; American Society for Biochemistry and Molecular Biology
• Subjects: Alzheimer disease; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Animals; drug screening; Entorhinal Cortex - metabolism; Entorhinal Cortex - pathology; human; Humans; Locus Coeruleus - metabolism; Locus Coeruleus - pathology; Microfluidic Analytical Techniques; microfluidics; microtubule; Models, Neurological; Neurobiology; neurodegeneration; neurodegenerative disease; neuron; Neurons - metabolism; Neurons - pathology; propagation; protein aggregation; Rats; Rats, Sprague-Dawley; Tau protein (Tau); tau Proteins - metabolism; tauopathy; Tissue Culture Techniques; microtubule; tauopathy; neurodegenerative disease; propagation; Tau protein (Tau); drug screening; Alzheimer disease; protein aggregation; neurodegeneration; neuron; human; microfluidics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA120.013325

Tau aggregation and hyperphosphorylation is a key neuropathological hallmark of Alzheimer's disease (AD), and the temporospatial spread of Tau observed during clinical manifestation suggests that Tau pathology may spread along the axonal network and propagate between synaptically connected neurons. Here, we have developed a cellular model that allows the study of human AD-derived Tau propagation from neuron to neuron using microfluidic devices. We show by using high-content imaging techniques and an in-house developed interactive computer program that human AD-derived Tau seeds rodent Tau that propagates trans-neuronally in a quantifiable manner in a microfluidic culture model. Moreover, we were able to convert this model to a medium-throughput format allowing the user to handle 16 two-chamber devices simultaneously in the footprint of a standard 96-well plate. Furthermore, we show that a small molecule inhibitor of aggregation can block the trans-neuronal transfer of Tau aggregates, suggesting that the system can be used to evaluate mechanisms of Tau transfer and find therapeutic interventions.