title: Nmnat2 attenuates Tau phosphorylation through activation of PP2A.
abstract: The activity of protein phosptase-2A (PP2A) is significantly decreased in the brains of Alzheimer's disease (AD) patients, but the upstream effectors for regulating PP2A activity are not fully understood. Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) is a key enzyme involved in energy metabolism and its gene expression level is reduced in AD brain specimens. Whether Nmnat2 can activate PP2A deserves to be explored. Here, we first measured the level of Nmnat2, Tyr307-phosphorylation of PP2A, and tau phosphorylation in Tg2576 mice. We observed that the mRNA and protein levels of Nmnat2 were significantly decreased with a simultaneous elevation of p-Tyr307-PP2A and tau phosphorylation in Tg2576 mice. Further studies in HEK293 cells with stable expression of human tau441 (HEK293/tau) demonstrated that simultaneous inhibition of PP2A by okadaic acid abolished the Nmnat2-induced tau dephosphorylation. Moreover, we further demonstrated that overexpression of Nmnat2 could activate PP2A with attenuation of tau phosphorylation, whereas downregulation of Nmnat2 by shRNA inhibited PP2A with tau hyperphosphorylation at multiple AD-associated sites. Our data provide the first evidence that Nmnat2 affects tau phosphorylation by regulating PP2A activity, suggesting that Nmnat2 may serve as a potential target in arresting AD-like tau pathologies.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Ministry of China, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiang-Shu
authors.initials: XS
authors.lastname: Cheng
authors.forename: Kun-Peng
authors.initials: KP
authors.lastname: Zhao
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.forename: Lai-Ling
authors.initials: LL
authors.lastname: Du
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Li
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Ma
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.forename: Dong-Xiao
authors.initials: DX
authors.lastname: Duan
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.forename: Xin-Wen
authors.initials: XW
authors.lastname: Zhou
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000502:physiology*; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D019319:Okadaic Acid; C484008:NMNAT2 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C579543:Nmnat2 protein, mouse; D054648:Protein Phosphatase 2