Fetal Tau Bias in iPSC -Derived Neurons, MAPT Mutant Mouse Models and Molecular Mechanisms Assessment for Integrative Analysis of Tau Pathology

Abstract

Tauopathies, such as Alzheimer's disease and Frontotemporal Dementia, are caused by complex interactions between tau isoform imbalance, MAPT mutations, and harmful post-translational modifications. Despite significant breakthroughs, current human cellular models may not accurately reflect adult tau biology, limiting mechanistic knowledge and therapeutic translation. In this review, we draw on new knowledge from stem cell platforms, MAPT mutant mice models, and multi-omics investigations to identify important gaps and stakes in modeling tau pathology. Recent efforts using CRISPR-engineered human stem cell lines, NGN3-induced i3 neurons, and patient-derived iPSCs show great promise, but they consistently retain a fetal-like predominance of 3-repeat (3R) tau, limiting the ability to recapitulate adult 3R/4R tau ratios and age-associated tauopathy phenotypes. Organoid and multi-cell co-culture methods (such as RenVM and tri-cellular constructions) boost microenvironmental complexity, but are limited by developmental immaturity and variable tau isoform flipping. Complementary MAPT knock-in and transgenic mice models (e.g., P301L, P301S, V337M, S320F) provide robust in vivo mechanisms for tau misfolding, seeding, and propagation, while also revealing species-specific compensatory processes that differ from human neurodegeneration. At the molecular level, mass spectrometry based phosphoproteomics has revealed a coordinated network of tau post-translational modifications; phosphorylation, acetylation, and ubiquitination that converge on proline-rich and C-terminal regions to cause tau detachment from microtubules and aggregate. These findings highlight the necessity for integrated models that can capture both isoform regulation and combinatorial PTM landscapes. Together, these findings highlight a key translational gap that most human model systems fail to reach adult tau maturation, as animal models cannot fully mimic human-specific tau biology. We propose a paradigm that integrates sophisticated stem cell engineering, MAPT mutation-aligned mice models, and multi-omics profiling to create next-generation platforms for understanding tauopathy processes and accelerating therapeutics development.