Dissertation
Tau-MAP6-microtubule axis as a driver for biphasic neurodegeneration in tauopathy-patient-derived cortical organoids
Doctor of Philosophy (Ph.D.), Drexel University
Nov 2024
DOI:
https://doi.org/10.17918/00010796
Abstract
In tauopathies like Frontotemporal Dementia (FTD), dysfunctional tau detaches from axonal microtubules (MTs) and forms neurofibrillary tangles. Although traditionally regarded as an MT stabilizer, tau is now understood to primarily promote and maintain labile MTs, challenging prior assumptions about its role as an MT stabilizer as well as MT destabilization in FTD. Conventional models -- relying on postmortem tissue and transgenic mice overexpressing human tau -- often miss early disease dynamics and are constrained by species-specific tau biology. To overcome these limitations, we employed FTD patient-derived human cortical organoids, a novel microphysiological system that recapitulates the complex cytoarchitecture of the human brain. This innovative platform enabled the first comprehensive analysis of MT deficits in tauopathy across two distinct tau mutations (tauP301S and tauP301L) in FTD-patient induced pluripotent stem cell (iPSC)-derived organoids and their corresponding CRISPR-Cas9-edited isogenic controls, revealing a consistent and reproducible biphasic pattern of MT defects. Early-stage tau mutant organoids exhibited increased MT dynamics (more labile MTs) and heightened neuronal activity, likely due to initially elevated functional tau, which could be partially mitigated by tau reduction. In contrast, late-stage tau mutant organoids, consistent with postmortem tissue from the FTD patients, showed reduced functional tau levels, decreased MT dynamics (more stable MTs), robust tau pathologies, and characteristic neurodegenerative features. Strikingly, MAP6, which directly binds and stabilizes MTs, displayed phase-dependent changes opposite to those of tau, suggesting a regulatory tau-MAP6-MT axis driving neurodegeneration in a stage-specific manner. This biphasic shift in the tau-MAP6-MT axis uncovers a novel MT-based mechanism underlying tauopathy, emphasizing the need for phase-dependent MT therapies for treatment. Furthermore, our findings validate the groundbreaking potential of human iPSC-derived organoids as an effective model for recapitulating dynamic and complex disease phenotypes for neurodegeneration.
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Details
- Title
- Tau-MAP6-microtubule axis as a driver for biphasic neurodegeneration in tauopathy-patient-derived cortical organoids
- Creators
- Xiaohuan Sun
- Contributors
- Liang Qiang (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xv, 194 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991021970901104721