Silencing PP2A inhibitor by lenti-shRNA interference ameliorates neuropathologies and memory deficits in tg2576 mice.
Deficits of protein phosphatase-2A (PP2A) play a crucial role in tau hyperphosphorylation, amyloid overproduction, and synaptic suppression of Alzheimer's disease (AD), in which PP2A is inactivated by the endogenously increased inhibitory protein, namely inhibitor-2 of PP2A (I2(PP2A)). Therefore, in vivo silencing I2(PP2A) may rescue PP2A and mitigate AD neurodegeneration. By infusion of lentivirus-shRNA targeting I2(PP2A) (LV-siI2(PP2A)) into hippocampus and frontal cortex of 11-month-old tg2576 mice, we demonstrated that expression of LV-siI2(PP2A) decreased remarkably the elevated I2(PP2A) in both mRNA and protein levels. Simultaneously, the PP2A activity was restored with the mechanisms involving reduction of the inhibitory binding of I2(PP2A) to PP2A catalytic subunit (PP2AC), repression of the inhibitory Leu309-demethylation and elevation of PP2AC. Silencing I2(PP2A) induced a long-lasting attenuation of amyloidogenesis in tg2576 mice with inhibition of amyloid precursor protein hyperphosphorylation and β-secretase activity, whereas simultaneous inhibition of PP2A abolished the antiamyloidogenic effects of I2(PP2A) silencing. Finally, silencing I2(PP2A) could improve learning and memory of tg2576 mice with preservation of several memory-associated components. Our data reveal that targeting I2(PP2A) can efficiently rescue Aβ toxicities and improve the memory deficits in tg2576 mice, suggesting that I2(PP2A) could be a promising target for potential AD therapies.
Department of Pathophysiology, Key Laboratory of the Ministry Education of China for Neurological Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Gong-Ping
GP
Liu
Wei
W
Wei
Xin
X
Zhou
Hai-Rong
HR
Shi
Xing-Hua
XH
Liu
Gao-Shang
GS
Chai
Xiu-Qing
XQ
Yao
Jia-Yu
JY
Zhang
Cai-Xia
CX
Peng
Juan
J
Hu
Xia-Chun
XC
Li
Qun
Q
Wang
Jian-Zhi
JZ
Wang
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D056488:Histone Chaperones; D006801:Humans; D016086:Lentivirus / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; C557500:SET protein, mouse; D016875:tau Proteins; D054648:Protein Phosphatase 2