Inhibition of Protein Phosphatase-2A (PP2A) by I 1 PP2A Leads to Hyperphosphorylation 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 neurofibrillary degeneration and cognitive deficits in rats.