Objective In the amyloidogenic pathway, cleavage of APP by β-secretase generates an N-terminal soluble fragment (sAPP) and beta C-terminal fragment that is sequentially cleaved by γ-secretase to produce the Aβ peptides.Threonine 668 (T668) in the cytoplasmic domain of APP can be phosphorylated in vivo by a number of protein kinases, including GSK-3β, CDK5, CDC2 and JNK etc.Many of these kinases are associated with neurotoxicity and implicated in neurodegenerative diseases.Kinases may play a key role in regulating the stability of APP, its interaction with intracellular partners and downstream signaling events.It has been well recognized that an imbalanced regulation in protein kinases and protein phosphatases is the direct cause for the AD pathogenesis.We doubt that PP2A which considered being involved in the pathogenesis of AD can affect phosphorylation of APP at T668 to regulate Aβ generation.Methods N2a cells stable transfected with human APP (N2a-APP) were transiently transfected with GFP-PP2AsiRNA and Dsred-PP2A, Forty-eight hours after transfection, the protein level of phosphor-APP and total APP were determined by immunobloting.The N2a-APP cells and the hippocampus of SD rats were also administrated with Okadaic acid (OA) or DES (c6-ceramide) by 24 hours.The Immunoblot was used to detect the level of phosphorAPP and APP.The Abeta level of cells and animals were detected by ELISA assay.Results (1) Inhibition of PP2A by OA or siRNA can increase the phosphorylation of APP.(2) Activation of PP2A by DES or overexpression seems not affect the level of phosphor-APP.(3) The incretion of phosphor-APP by OA may not only owe to PP2A.PP1 as an important phosphatases inhibited by OA may play a role in phosphorylation of APP and Abeta secretion.(4) The Aβ level increased after injection on hippocampus of SD rats with 0.6 μM OA.Conclusion These results indicated that PP2A which considered to be involved in the pathogenesis of AD can affect phosphorylation of APP at T668 to regulate Aβ generation.