Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic Mice
Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic Mice
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DOI：
10.1523/jneurosci.4264-11.2012
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发表时间：
2012-02-08
影响因子：
5.3
通讯作者：
Matsuoka, Nobuya
中科院分区：
文献类型：
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作者：
Mitani, Yasuyuki;Yarimizu, Junko;Matsuoka, Nobuya
γ-分泌酶抑制剂（GSI）减少淀粉样蛋白-β（A β）肽，但不可避免地增加淀粉样蛋白前体蛋白（APP）的β-C-末端片段（β-CTF），潜在地对突触具有不良影响。相反，γ-分泌酶调节剂（GSM）减少A β 42而不增加β-CTF。虽然这些化合物的A β降低作用已被广泛研究，但很少有人研究它们对认知的影响。在此，我们比较了两种GSI-（2S）-2-羟基-3-甲基-N-[（2S）-1-{[（1 S）-3-甲基-2-氧代-2，3，4，5-四氢-1H-3-苯并氮杂卓-1-基]氨基}-1-氧代丙-2-基]丁酰胺（LY 450139，semagacestat）和（2 R）-2-[[（4-氯苯基）磺酰基][[2-氟-4-（三氟甲基）苯基]磺酰基]（1，2，4-恶唑-3-基）苯基]甲基氨基-5，5，5-三氟戊酰胺（BMS-708163）-和第二代GSM [{（2S，4 R）-1-[（4 R）-1，1，1-三氟-7-甲基辛-4-基]-2-[4-（三氟甲基）苯基]-2-（三氟甲基）-1H-吡唑并[3，4-d]嘧啶（三氟甲基）苯基]哌啶-4-基}乙酸（GSM-2）]对APP转基因小鼠（Tg 2576）和非转基因小鼠空间工作记忆的影响。虽然急性给药与GSI改善记忆缺陷在5.5个月大的Tg 2576小鼠，这些影响消失后8天亚慢性给药。亚慢性给药任一GSI均会损害3月龄Tg 2576小鼠的正常认知，而不会抑制大脑中其他γ-分泌酶底物（如Notch、N-钙粘蛋白或EphA 4）的加工。LY 450139也损害野生型小鼠的正常认知;然而，效力比Tg 2576小鼠低10倍，表明APP依赖性机制可能与β-CTF积累有关。免疫荧光研究表明，β-CTF积累定位于海马透明层和齿状门的突触前末梢，这意味着对苔藓纤维中突触前功能的影响。相比之下，GSM-2的急性和亚慢性给药均显著改善了Tg 2576小鼠的记忆缺陷，并且不影响野生型小鼠的正常认知。我们证明了GSI和GSM在对功能后果的影响方面存在明显差异，为开发这些抗阿尔茨海默病药物的策略提供了新的见解。
gamma-Secretase inhibitors (GSIs) reduce amyloid-beta (A beta) peptides but inevitably increase the beta-C-terminal fragment (beta-CTF) of amyloid precursor protein (APP), potentially having undesirable effects on synapses. In contrast, gamma-secretase modulators (GSMs) reduce A beta 42 without increasing beta-CTF. Although the A beta-lowering effects of these compounds have been extensively studied, little effort has been made to investigate their effects on cognition. Here, we compared the effects of two GSIs-(2S)-2-hydroxy-3-methyl-N-[(2S)-1-{[(1S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]amino}-1-oxopropan-2-yl]butanamide (LY450139, semagacestat) and (2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxazol-3-yl)phenyl]methyllamino-5,5,5-trifluoropentanamide (BMS-708163)-and a second-generation GSM [{(2S,4R)-1-[(4R)-1,1,1-trifluoro-7-methyloctan-4-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetic acid (GSM-2)] on spatial working memory in APP-transgenic (Tg2576) and nontransgenic mice using the Y-maze task. While acute dosing with either GSI ameliorated memory deficits in 5.5-month-old Tg2576 mice, these effects disappeared after 8 d subchronic dosing. Subchronic dosing with either GSI rather impaired normal cognition in 3-month-old Tg2576 mice, with no inhibition on the processing of other gamma-secretase substrates, such as Notch, N-cadherin, or EphA4, in the brain. LY450139 also impaired normal cognition in wild-type mice; however, the potency was 10-fold lower than that in Tg2576 mice, indicating an APP-dependent mechanism likely with beta-CTF accumulation. Immunofluorescence studies revealed that the beta-CTF accumulation was localized in the presynaptic terminals of the hippocampal stratum lucidum and dentate hilus, implying an effect on presynaptic function in the mossy fibers. In contrast, both acute and subchronic dosing with GSM-2 significantly ameliorated memory deficits in Tg2576 mice and did not affect normal cognition in wild-type mice. We demonstrated a clear difference between GSI and GSM in effects on functional consequences, providing new insights into strategies for developing these drugs against Alzheimer's disease.