title: Inhibition of Protein Phosphatase-2A (PP2A) by I1PP2A Leads to Hyperphosphorylation of Tau, Neurodegeneration, and Cognitive Impairment in Rats.
abstract: 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 (I(1)(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 I(1)(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 I(1)(PP2A). In the adult AAV1-I(1)(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- I(1)(PP2A) animals, suggesting that I(1)(PP2A) can induce a loss of dendritic and synaptic plasticity markers. Behavioral tests revealed that infection with AAV1- I(1)(PP2A) induced deficits in exploratory activity, spatial reference memory, and memory consolidation in adult rats. These studies suggest that I(1)(PP2A) can inhibit PP2A activity, and in turn induce AD neurofibrillary degeneration and cognitive deficits in rats.
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
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, NY, USA.
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, NY, USA.
authors.forename: Yunn Chyn
authors.initials: YC
authors.lastname: Tung
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
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, NY, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D041681:NIH 3T3 Cells; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D016874:Neurofibrillary Tangles; D009460:Neurologic Examination; D009687:Nuclear Proteins; D010766:Phosphorylation / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D051381:Rats; D017208:Rats, Wistar; D016704:Synapsins / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C087425:ANP32A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D016704:Synapsins; D016875:tau Proteins; D054648:Protein Phosphatase 2
keywords: Inhibitor I of PP2A ($I_{1}^{PP2A}$); neurofibrillary degeneration; protein phosphatase-2A (PP2A); tau hyperphosphorylation