Transmission of tauopathy strains is independent of their isoform composition.

The deposition of pathological tau is a common feature in several neurodegenerative tauopathies. Although equal ratios of tau isoforms with 3 (3R) and 4 (4R) microtubule-binding repeats are expressed in the adult human brain, the pathological tau from different tauopathies have distinct isoform compositions and cell type specificities. The underlying mechanisms of tauopathies are unknown, partially due to the lack of proper models. Here, we generate a new transgenic mouse line expressing equal ratios of 3R and 4R human tau isoforms (6hTau mice). Intracerebral injections of distinct human tauopathy brain-derived tau strains into 6hTau mice recapitulate the deposition of pathological tau with distinct tau isoform compositions and cell type specificities as in human tauopathies. Moreover, through in vivo propagation of these tau strains among different mouse lines, we demonstrate that the transmission of distinct tau strains is independent of strain isoform compositions, but instead intrinsic to unique pathological conformations. Although normal human brains express 6 tau isoforms in equal ratio with 3 or 4 microtubule-binding repeat domains (3R and 4R), tau inclusions from different human tauopathy brains, now considered as different strains, have distinct isoform compositions and strain properties and the relationship between these two parts is unclear. Here the authors generate a new transgenic mouse line expressing 6 human tau isoforms with equal 3R and 4R ratios, recapitulate distinct human tau strains in mouse brains with similar isoform compositions and cell type specificities, and further show the strain transmission pattern is independent of its isoform composition.