A murine model of amyloid-enhanced tauopathy: Comparison of wild-type and P301L-tau.

introductionTo optimize a model of amyloid-enhanced tauopathy we compared wild-type (WT) tau with P301L-tau in a mouse with mature amyloid.

methodsMice transgenic for amyloid precursor protein and presenilin-1 (APP+PS1, A/P) were injected intravenously with adeno-associated virus with capsid B10 (AAV.CAP-B10) expressing either WT or P301L human tau. Mice were behaviorally assessed 5 and 8 months and tissue collected 9 months after injection.

resultsA/P+WT and A/P+P301L groups were equivalently impaired in spatial learning and memory. A/P+WT mice had significantly greater tau hyperphosphorylation than A/P+P301L mice. However, A/P+P301L mice had greater deposition of phospho-tau and formation of Gallyas-positive neurofibrillary tangles (NFTs). DISCUSSION: These data demonstrate that WT-tau is more highly phosphorylated than P301L-tau in the presence of amyloid in mouse brain. Furthermore, despite the lack of NFT pathology in A/P+WT mice, WT-tau still caused cognitive impairment. The use of WT-tau in this model may make it more translatable for pre-clinical assessments of potential therapeutics for AD.