Distinct mechanistic pathways of early tauopathy revealed by MAPT mutations

Distinct mechanistic pathways of early tauopathy revealed by MAPT mutations | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Distinct mechanistic pathways of early tauopathy revealed by MAPT mutations Martha Foiani, Raja Nirujogi, Naoto Watamura, Sumi Bez, Eliona Tsefou, and 25 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8751712/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Tau pathology underlies a broad spectrum of neurodegenerative disorders, collectively termed tauopathies, yet these diseases exhibit striking heterogeneity in their biological mechanisms and clinical outcomes. The basis for this heterogeneity remains poorly understood. Here, we address this question using knock-in mouse models expressing two distinct frontotemporal dementia-associated tau mutations to define how different tau variants drive divergent pathogenic programs in vivo. We find that the two mutations give rise to fundamentally different trajectories of tau pathogenesis. One trajectory is marked by progressive tau hyperphosphorylation and cytoskeletal destabilization occurring in the absence of detectable tau seed formation. In contrast, an alternative trajectory is characterized by tau hypophosphorylation, early seed formation, and alterations in nucleotide metabolism and chromatin organization, without overt cytoskeletal disruption. With aging, tau in this latter pathway transitions to a hyperphosphorylated state and forms mature fibrillar aggregates. Genetic enhancement of β-amyloid selectively accelerates fibril formation, particularly in the model exhibiting early seeding. Together, these findings demonstrate that distinct tau mutations can engage separable pathogenic mechanisms, providing a biological framework for the heterogeneity observed across tauopathies and highlighting the need for mechanism-informed therapeutic strategies and patient stratification. Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease Biological sciences/Neuroscience/Cellular neuroscience Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TableS5.pdf Supplemental Table 5 TableS2.pdf Supplemental Table 2 TableS6.pdf Supplemental Table 6 SupplementaryFig.2.pdf Supplemental Figure 2 Graphicalabstract.pdf Figure 7 SupplementaryFig4.pdf Supplemental Figure 4 SupplementaryFig5.pdf Supplemental Figure 5 TableS4.pdf Supplemental Table 4 SupplementaryFig6.pdf Supplemental Figure 6 tableS3.pdf Supplemental Table 3 SupplementaryFig.1.pdf Supplemental Figure 1 TableS1.pdf Supplemental Table 1 SupplementaryFig.7.pdf Supplemental Figure 7 supplementaryFig3.pdf Supplemental Figure 3 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

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