Deficiency of protein phosphatase-2A is a key event in Alzheimer's disease. An 
endogenous inhibitor of protein phosphatase-2A, inhibitor-1, I1PP2A, which 
inhibits the phosphatase activity by interacting with its catalytic subunit 
protein phosphatase-2Ac, is known to be upregulated in Alzheimer's disease 
brain. In the present study, we overexpressed I1PP2A by intracerebroventricular 
injection with adeno-associated virus vector-1-I1PP2A in Wistar rats. The I1PP2A 
rats showed a decrease in brain protein phosphatase-2A activity, abnormal 
hyperphosphorylation of tau, neurodegeneration, an increase in the level of 
activated glycogen synthase kinase-3beta, enhanced expression of intraneuronal 
amyloid-beta and spatial reference memory deficit; littermates treated 
identically but with vector only, i.e., adeno-associated virus vector-1-enhanced 
GFP, served as a control. Treatment with memantine, a noncompetitive NMDA 
receptor antagonist which is an approved drug for treatment of Alzheimer's 
disease, rescued protein phosphatase-2A activity by decreasing its demethylation 
at Leu309 selectively and attenuated Alzheimer's disease-like pathology and 
cognitive impairment in adeno-associated virus vector-1-I1PP2A rats. These 
findings provide new clues into the possible mechanism of the beneficial 
therapeutic effect of memantine in Alzheimer's disease patients.