Abstract Body

We have tested several human tau mutation variants and the common variant (wild type) for their capacity to produce tauopathy in middle aged mice. Twelve month old C57BL/6Nia mice were injected with AAV serotype 9 vectors expressing either wild type human tau, P301L tau, R406W tau or GFP (control) into the anterior cortices and hippocampus bilaterally. Mice injected with tau variants also were injected with a 1/10^th dose of the GFP virus to control for injection variability. Both P301L and wild type injected mice exhibited memory deficits in radial arm water maze performance 4 months later. Detergent soluble total tau was lower in the R406W mice than the other tau variant injected groups, yet GFP expression was elevated in this group, suggesting this variant impaired tau expression. Insoluble total tau was greatest in the P301L injected group. Soluble p-199-tau and p-396-tau were highest in the wild type mice, while insoluble p-tau and Gallyas staining were highest in the P301L mice. Remarkably, the only group demonstrating hippocampal atrophy was the wild type injected mice, with a mean 40% reduction in hippocampal volume. These data suggest that even though P301L increased insoluble, silver positive tau deposits, wild type tau with large amounts of soluble tau isoforms was more toxic to the hippocampus. Supported by AG 051500 to DM and AG062217 to MNG