title: Memantine Attenuates Alzheimer's Disease-Like Pathology and Cognitive Impairment.
abstract: 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.
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.|Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Blanchard
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D003072:Cognition Disorders / Q000188:drug therapy*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology*; D009687:Nuclear Proteins; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D016601:RNA-Binding Proteins; D051381:Rats; D017208:Rats, Wistar
chemical_list: C087425:ANP32A protein, human; D015259:Dopamine Agents; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D054648:Protein Phosphatase 2; D008559:Memantine