The carboxy-terminal fragment of inhibitor-2 of protein phosphatase-2A induces Alzheimer disease pathology and cognitive impairment.
Development of rational therapeutic treatments of Alzheimer disease (AD) requires the elucidation of the etiopathogenic mechanisms of neurofibrillary degeneration and β-amyloidosis, the two hallmarks of this disease. Here we show, employing an adeno-associated virus serotype 1 (AAV1)-induced expression of the C-terminal fragment (I(2CTF)) of I(2)(PP2A), also called SET, in rat brain, decrease in protein phosphatase 2A (PP2A) activity, abnormal hyperphosphorylation of tau, and neurodegeneration; littermates treated identically but with vector only, i.e., AAV1-enhanced green fluorescent protein (GFP), served as a control. Furthermore, there was an increase in the level of activated glycogen synthase kinase-3β and enhanced expression of intraneuronal Aβ in AAV1-I(2CTF) animals. Morris water maze behavioral test revealed that infection with AAV1-I(2CTF) induced spatial reference memory and memory consolidation deficits and a decrease in the brain level of pSer133-CREB. These findings suggest a novel etiopathogenic mechanism of AD, which is initiated by the cleavage of I(2)(PP2A), producing I(2CTF), and describe a novel disease-relevant nontransgenic animal model of AD.
Wang
Xiaochuan
X
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Blanchard
Julie
J
Kohlbrenner
Erik
E
Clement
Nathalie
N
Linden
R Michael
RM
Radu
Aurelian
A
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D000256:Adenoviridae / Q000235:genetics; D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003072:Cognition Disorders / Q000473:pathology*; D003712:Dendrites / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics; D013569:Synapses / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; C554285:SET protein, rat; D016875:tau Proteins; D049452:Green Fluorescent Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2