Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Patient-derived forebrain cortical organoids reveal biphasic tau-MAP6-microtubule axis dysfunction in tauopathy.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Sun Xiaohuan, Ramakrishnan Skandha, Ogbolu Victor C, Kanaan Nicholas M, Karch Celeste M, Baas Peter W, Qiang Liang
Аннотация
INTRODUCTION: 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.
METHODS: Human induced pluripotent stem cells carrying MAPTWT/P301L, MAPTWT/P301S, or MAPTWT/R406W 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.
RESULTS: 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.
DISCUSSION: This work reveals a biphasic tau-MAP6-microtubule mechanism driving tauopathy and establishes these organoids as a platform for phase-specific therapy.
METHODS: Human induced pluripotent stem cells carrying MAPTWT/P301L, MAPTWT/P301S, or MAPTWT/R406W 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.
RESULTS: 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.
DISCUSSION: This work reveals a biphasic tau-MAP6-microtubule mechanism driving tauopathy and establishes these organoids as a platform for phase-specific therapy.