Pronounced microgliosis and neurodegeneration in aged rats after tau gene transfer

Microtubule-associated protein tau gene transfer to the substantia nigra of rats using the adeno-associated virus (AAV) vector previously led to neuropathology and neurodegeneration in young rats. In this study, we compared equal tau gene transfer in either 3 or 20-month-old rats, in order to test the hypothesis that late middle-aged rats are more susceptible to neurodegeneration. Two intervals and two vector doses of the tau vector probed for age-related differences in the initial sensitivity to low-level tau expression. Gene transfer efficiency was similar for both ages, but the tau vector caused more dopaminergic cell loss and a greater behavioral deficit in aged rats at specific doses and time points. Tau gene transfer caused microgliosis relative to the control vector, and to a greater extent in aged rats. The maximal microglial response occurred at 2 weeks preceding the peak dopaminergic cell loss by 8 weeks. The cellular and behavioral outcomes were more severe in the aged rats, validating the model for studies of age-related diseases.