Substrate-specific reduction of PP2A activity exaggerates tau pathology.
Phosphorylation of the microtubule-associated protein tau is regulated by the balanced interplay of kinases and phosphatases. Disturbance of this balance causes hyperphosphorylation of tau and neurofibrillary tangle formation in Alzheimer's disease brain. Here, we crossed Dom5 mice that express a substrate-specific dominant negative mutant form, L309A Calpha, of protein phosphatase 2A (PP2A) with neurofibrillary-tangle-forming P301L mutant tau transgenic pR5 mice. This exacerbated the tau pathology of pR5 mice significantly. Double-transgenic Dom5/pR5 mice showed 7-fold increased numbers of hippocampal neurons that specifically phosphorylated the pathological S422 epitope of tau. They showed 8-fold increased numbers of tangles compared to pR5 mice, in agreement with our previous finding that tangle formation is correlated with and preceded by phosphorylation of tau at the S422 epitope. This suggests that, in addition to kinases, PP2A and its regulatory subunits may be a therapeutic target for Alzheimer's disease.
Deters
Natasha
N
Alzheimer's and Parkinson's Disease Laboratory, Brain and Mind Research Institute, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia.
Ittner
Lars M
LM
Götz
Jürgen
J
D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013379:Substrate Specificity; D016875:tau Proteins / Q000378:metabolism*
C054369:MAPT protein, human; D021122:Protein Subunits; D016875:tau Proteins; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2