Adeno-Associated Viral Gene Delivery of Wild-Type Human Tau Induces Progressive Hyperphosphorylation and Neuronal Cell Death in the Hippocampi of Middle-Aged Rats.

Tau aggregation and the subsequent formation of neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) and other dementias. While accumulation of tau aggregates is believed to contribute to cell death and neurodegeneration, tau aggregation and hyperphosphorylation are also correlated with cognitive impairment in AD. To understand the role of tau in neurodegeneration, we used adeno-associated virus serotype 9 (AAV9) to express human wild-type 4-repeat, 0-N-terminus tau isoform (AAV-htau) in the Cornu ammonis area 1 (CA1) region of the dorsal hippocampus of adult 6-month-old Fischer 344 rats. AAV expressing green fluorescent protein (AAV-GFP) or uninjected rats were used as controls. To characterize early phenotypes, we investigated pathological changes at 3, 8, and 12 weeks post-injection of AAV-htau. Our results show that at 3 weeks post-injection, there was already robust expression of human tau in the CA1 region of animals injected with AAV-htau compared to those injected with AAV-GFP or the uninjected controls. At 12 weeks post-injection, area CA1 showed a statistically significant reduction in cell number and a thinner neuronal layer all throughout the anterior dorsal hippocampus, as well as redistribution to the somatodendritic areas of CA1. We also found hyperphosphorylation of tau at all three timepoints. In spite of this pathology, we did not find any hippocampal-dependent cognitive impairment in rats overexpressing human tau. These results provide evidence of AAV-htau as a progressive model of tauopathy pathology to study changes in phosphorylation status and neuronal cell death that might precede cognitive impairment.