of Tau, Neurodegeneration, and Cognitive Impairment in Rats

Protein phosphatase-2A (PP2A) deficiency is a cause of the abnormal hyperphosphorylation of tau, which composes neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. We previously reported that both mRNA and protein expression of inhibitor I of PP2A (I1 PP2A ) are elevated in AD brain and that this inhibitor induces a dose-dependent inhibition of PP2A activity and tau hyperphosphorylation in NIH3T3 cells. However, whether I1 PP2A can induce AD neurofibrillary degeneration and cognitive impairment was not known. In the present study, we infected the brains of rat pups within 24 hours of birth with adeno-associated virus serotype 1 (AAV1) carrying I1 PP2A. In the adult AAV1-I1 PP2A rats, we found a decrease in PP2A activity and abnormal hyperphosphorylation of tau in the brain. Immunohistochemistry showed a significant reduction of MAP2 and synapsin 1 in AAV1- I1 PP2A animals, suggesting that I1 PP2A can induce a loss of dendritic and synaptic plasticity markers. Behavioral tests revealed that infection with AAV1- I1 PP2A induced deficits in exploratory activity, spatial reference memory, and memory consolidation in adult rats. These studies suggest that I1 PP2A can inhibit PP2A activity, and in turn induce AD