Focal expression of adeno-associated viral-mutant tau induces widespread impairment in an APP mouse model.

Adeno-associated virus serotype 6 (AAV6) viral vectors encoding mutant and normal tau were used to produce focal tau pathology. Two mutant forms of tau were used; the P301S tau mutation is associated with neurofibrillary tangle formation in humans, and the 3PO mutation leads to rapid tau aggregation and is associated with pathogenic phosphorylation and cytotoxicity in vitro. We show that adeno-associated viral injection into entorhinal cortex of normal and tau knockout animals leads to local overexpression of tau, and the presence of human tau in axons projecting to and emanating from the entorhinal cortex. Starting at 2 months and increasing by 6 months post-injection neurons expressing mutant tau developed hyperphosphorylated tau pathology, in addition to dystrophic neurites. There was neuronal loss in tau-expressing regions, which was similar in normal and in TASTPM mice injected with mutant tau. There was neuroinflammation around plaques, and in regions expressing mutant tau. We saw no evidence that mutant tau had affected amyloid-beta pathology or vice versa. Morris water maze behavioral tests demonstrated mild memory impairment attributable to amyloid-beta pathology at 2 and 4 months, with severe impairment at 6 months in animals receiving adeno-associated viral-3PO. Therefore, TASTPM mice injected with mutant tau displayed many of the main features characteristic of human Alzheimer's disease patients and might be used as a model to test new drugs to ameliorate clinical features of Alzheimer's disease.