Journal article
Patient-derived forebrain cortical organoids reveal biphasic tau-MAP6-microtubule axis dysfunction in tauopathy
Alzheimer's & dementia, v 22(7), e71565
Jul 2026
PMID: 42411568
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
In frontotemporal dementia (FTD), tau detaches from axonal microtubules and forms pathological aggregates. Rather than stabilizing microtubules, tau promotes labile microtubule domains, redefining its role in neurodegeneration and underscoring the need for human models that capture temporal disease progression.
Human induced pluripotent stem cells carrying MAPT
, MAPT
, or MAPT
mutations and isogenic controls were differentiated into forebrain cortical organoids (1 to 8 months). Tau isoforms, microtubule dynamics, MAP6 regulation, neuronal activity, tau mRNA stability, and tau pathology were analyzed using biochemical, imaging, and electrophysiological approaches, some of which were benchmarked to postmortem behavorial variant FTD cortex.
Early-phase tau mutant organoids showed elevated tau, hyperdynamic microtubules, and neuronal hyperexcitability, partially reversible by tau reduction. Late-phase organoids exhibited insoluble tau accumulation, microtubule hyperstability, and neurodegeneration and reactive astrocytes, accompanied by opposing, phase-dependent MAP6 changes.
This work reveals a biphasic tau-MAP6-microtubule mechanism driving tauopathy and establishes these organoids as a platform for phase-specific therapy.
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Details
- Title
- Patient-derived forebrain cortical organoids reveal biphasic tau-MAP6-microtubule axis dysfunction in tauopathy
- Creators
- Xiaohuan Sun - Drexel UniversitySkandha Ramakrishnan - Drexel UniversityVictor C Ogbolu - Drexel UniversityNicholas M Kanaan - Michigan Center for Translational PathologyCeleste M Karch - Washington University in St. LouisPeter W Baas - Drexel UniversityLiang Qiang (Corresponding Author) - Drexel University
- Publication Details
- Alzheimer's & dementia, v 22(7), e71565
- Publisher
- Wiley; HOBOKEN
- Number of pages
- 20
- Grant note
- SAP#4100083087(LQ) / CURE program from Drexel University College of Medicine ResearchGrant(LQ) / Lisa Dean Moseley Foundation 24AARG-D-1191264(LQ) / Alzheimer's Association R21AG068597(PB) / NIA NIH HHS P30AG066444(CK) / NIA NIH HHS W81XWH2110189(PB) / U.S. Department of Defense R01NS115977(LQ) / NINDS NIH HHS R01NS110890-02(CK) / NINDS NIH HHS (CK) / Rainwater Charitable Organization R01NS082730(NK) / NIA NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; College of Medicine
- Web of Science ID
- WOS:001812617800001
- Other Identifier
- 991022194937204721
UN Sustainable Development Goals (SDGs)
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Clinical Neurology