Comparative Analysis of Primary (3R/4R) versus Secondary (3R + 4R) Tauopathy Strains in Rodent Models: A Systematic Review

Background Tauopathies are a heterogeneous group of neurodegenerative disorders characterized by a pathological tau aggregation. Each disorder is defined by distinct isoform content (3R, 4R, or mixed 3R/4R), which dictates cell-type susceptibility, pathologic propagation, and clinical symptomatology. How these strains propagate in vivo will be critical to developing translational models and therapies. Methods Following SWiM guidelines, we performed a systematic review with the protocol registered on PROSPERO (CRD420251053445). PubMed, Scopus, and Web of Science (inception - May 2025) searches identified studies directly comparing human brain-derived primary and secondary tau seeds in rodent models. Inclusion criteria required stereotactic intracerebral inoculation, comparable protocols, and reporting of inclusion burden, propagation, or isoform recruitment. SYRCLE tool was employed to assess the risk of bias. Results From the 1,437 screened records, 8 studies were eligible. Propagation in various rodent models was strain consistent: 4R-dominant seeds (CBD, PSP) selectively induced glial inclusions, while mixed AD-derived seeds induced neuronal neurofibrillary tangles with associated neurotoxicity. Isoform-selective recruitment, protease resistance to cleavage at particular sites, and amyloid-binding provided biochemical counterparts of tropism. Serial passage experiments confirmed heritability of strain features. Functional consequences included synaptic dysfunction, gliosis, and neuronal loss, whose spread patterns were host genotype- and time-of-observation-dependent. Risk-of-bias was mixed, with frequent unclear domains. Conclusion These findings support a two-way model in which tau strain conformation dictates cellular tropism, and host biology controls magnitude and distribution, and reinforce the prion-like model of tau transmission. Future work needs to prioritize standardized protocols, advanced humanized models, and multimodal functional readouts.