Data from: A human iPSC model of tauopathies engineered for 4R tau isoform expression endogenously develops late-stage neuronal tau pathology

Tauopathies, such as Alzheimer’s disease and Frontotemporal Dementia, are
common neurodegenerative diseases characterized by misfolding,
hyperphosphorylation, and aggregation of Tau. Molecular mechanisms
underlying Tauopathies are still poorly understood, in part due to a lack
of human models endogenously developing major disease hallmarks. Adult Tau
isoform expression contributes to Tau pathogenesis but is challenging to
replicate in human stem-cell-derived systems, which impedes the formation
of late-stage disease phenotypes and, hence, the research on underlying
mechanisms and drug development. Here, we show that induction of adult
human brain-like 4R Tau isoform expression enables endogenous formation of
late-stage Tauopathy hallmarks in iPSC-derived neurons engineered to
contain synergistic Tau mutations. Neurons accumulated seeding-competent,
hyper-phosphorylated, fibrillar Tau in tangle-like structures.
Furthermore, exclusive expression of mutant 4R in the absence of the 3R
Tau isoform disproportionately intensified pathology, resulting in highly
abundant Tau misfolding and aggregation. Finally, we provide
proof-of-principle that our model can be translationally applied both to
test chemical disease modulators and evaluate a human Tau PET tracer.
Collectively, our model enables novel investigations on endogenous
mechanisms of human Tauopathy formation, suggesting a central role of 4R
Tau isoform expression for pathogenesis in human neurons. Moreover, it may
also serve as a platform supporting urgently needed development of
disease-modifying drugs.