Intrahippocampal delivery of hyperphosphorylated human tau oligomers induces neurodegeneration in non-transgenic wildtype mice

Hyperphosphorylated tau (p-tau) forms neurofibrillary tangles, a key biomarker for Alzheimer’s disease and additional neurodegenerative tauopathies. However, neurofibrillary tangles are not sufficient to cause neuronal dysfunction or death. Intrahippocampal injection of tau isolated from AD patients has limited effects on the cognitive functions of non-transgenic mice, despite the recapitulation of pathological tau deposits in the mouse brain. It therefore remains uncertain as to whether all hyperphosphorylated tau is directly responsible for AD neurodegeneration. We examined this issue by injecting recombinant p-tau oligomers to the hippocampus of non-transgenic, wildtype mice and found progressive cognitive deficits that correlate with neuron death spreading from the ipsilateral hippocampus to the cortex. Apomorphine, which retards p-tau aggregation and cytotoxicity in vitro , antagonized p-tau-induced cognitive deficits and neuron death. These results suggest the pathogenic role of p-tau oligomers and a novel AD model facilitating drug development.