Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity

被引:54
作者
yi, Jee Hyun [1 ]
Baek, Soo Ji [2 ]
Heo, Sunghoo [2 ]
Park, Hye Jin [3 ]
Kwon, Huiyoung [3 ]
Lee, Seungheon [4 ]
Jung, Jiwook [5 ]
Park, Se Jin [6 ]
Kim, Byung C. [2 ]
Lee, Young Choon [3 ,9 ]
Ryu, Jong Hoon [7 ,8 ]
Kim, Dong Hyun [3 ,9 ]
机构
[1] Univ Bristol, Fac Med & Dent, Sch Clin Sci, Bristol, Avon, England
[2] Chonnam Natl Univ, Dept Neurol, Med Sch, Gwangju, South Korea
[3] Dong A Univ, Coll Hlth Sci, Dept Med Biotechnol, Busan, South Korea
[4] Jeju Natl Univ, Coll Ocean Sci, Sch Marine Biomed Sci, Dept Aquat Biomed Sci, Jeju, South Korea
[5] Daegu Haany Univ, Coll Herbal Bioind, Dept Herbal Med Pharmacol, Kyungsan, South Korea
[6] Kangwon Natl Univ, Sch Nat Resources & Environm Sci, Chunchon, South Korea
[7] Kyung Hee Univ, Coll Pharm, Dept Oriental Pharmaceut Sci, 1 Hoeki Dong, Seoul, South Korea
[8] Kyung Hee Univ, Dept Life & Nanopharmaceut Sci, 1 Hoeki Dong, Seoul, South Korea
[9] Dong A Univ, Inst Convergence Biohlth, Busan, South Korea
基金
新加坡国家研究基金会;
关键词
Amyloid beta; Alzheimer's disease; Akt; Long-term potentiation; Memory; GLYCOGEN-SYNTHASE KINASE-3-BETA; AMYLOID BETA-PEPTIDE; SIGNALING PATHWAY; TAU HYPERPHOSPHORYLATION; INDUCED NEUROTOXICITY; PC12; CELLS; OLIGOMERS; DYSFUNCTION; KINASE; BRAIN;
D O I
10.1016/j.neuropharm.2017.10.028
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Amyloid beta (A beta) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of A beta is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD-associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus-dependent memory impairments using A beta-injected as well as 5XFAD AD model mice. Oligomeric A beta injections into the 3rd ventricle caused concentration-dependent and time dependent impairments in learning/memory and synaptic plasticity. Moreover, A beta aberrantly regulated caspase-3, GSK-3 beta, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3 beta inhibitor ameliorated memory impairments and synaptic deficits in A beta-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both A beta-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD. (C) 2017 Elsevier Ltd. All rights reserved.
引用
收藏
页码:282 / 292
页数:11
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