Abstract
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 MAPT
WT/P301L, MAPT
WT/P301S, or MAPT
WT/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.
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This post is Copyright: | July 7, 2026
Neuro-Dementia