Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer's disease transgenic mice.
Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer's disease transgenic mice.
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DOI：
10.1111/j.1471-4159.2010.06608.x
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发表时间：
2010-04
影响因子：
4.7
通讯作者：
Ohno M
中科院分区：
文献类型：
--
作者：
Kimura R;Devi L;Ohno M
β位点淀粉样前体蛋白裂解酶1(BACE1)启动淀粉样蛋白(Aβ，Aβ)的生成，在阿尔茨海默病(AD)的病理生理学中起核心作用。因此，通过操纵BACE1降低Aβ水平是一种关键的治疗策略，但仍不清楚部分抑制BACE1是否能改善记忆障碍，正如AD治疗所预期的那样。在这项研究中，我们使用杂合子BACE1基因敲除(BACE1+/−)小鼠来评估部分抑制BACE1对阿尔茨海默病转基因小鼠(5XFAD模型)不同类型突触和认知功能障碍的影响。我们发现，~50%的BACE1减少不仅挽救了5XFAD小鼠在情境恐惧条件反射和自发交替Y迷宫范式中测试的海马区依赖记忆的缺陷，而且还挽救了语境条件作用30天后皮质依赖远程记忆稳定的缺陷。此外，在BACE1+/−·5XFAD小鼠中，5XFAD相关的长时程增强(学习和记忆的突触模型)的损伤和突触可塑性/学习相关的BDNFtrkB信号通路的下降被阻止。最后，这些改善与β分泌酶裂解的C-末端片段(C99)、Aβ多肽水平和BACE1+/−·5XFAD小鼠相关脑区斑块负荷的减少有关。因此，我们的发现为部分抑制BACE1的方法对与AD相关的多种形式的功能缺陷的有益效果提供了令人信服的证据。
β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) generation that is central to the pathophysiology of Alzheimer’s disease (AD). Therefore, lowering Aβ levels by BACE1 manipulations represents a key therapeutic strategy, but it remains unclear whether partial inhibition of BACE1, as expected for AD treatments, can improve memory deficits. In this study, we used heterozygous BACE1 gene knockout (BACE1+/−) mice to evaluate the effects of partial BACE1 suppression on different types of synaptic and cognitive dysfunctions in Alzheimer’s transgenic mice (5XFAD model). We found that ~50% BACE1 reductions rescued deficits of 5XFAD mice not only in hippocampus-dependent memories as tested by contextual fear conditioning and spontaneous alternation Y-maze paradigms but also in cortex-dependent remote memory stabilization during 30 days after contextual conditioning. Furthermore, 5XFAD-associated impairments in long-term potentiation (a synaptic model of learning and memory) and declines in synaptic plasticity/learning-related BDNF-TrkB signaling pathways were prevented in BACE1+/−·5XFAD mice. Finally, these improvements were related with reduced levels of β-secretase-cleaved C-terminal fragment (C99), Aβ peptides and plaque burden in relevant brain regions of BACE1+/−·5XFAD mice. Therefore, our findings provide compelling evidence for beneficial effects of partially BACE1-inhibiting approaches on multiple forms of functional defects associated with AD.
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影响因子：
56.9
作者：
Frankland, PW;Bontempi, B;Silva, AJ
通讯作者：
Silva, AJ
影响因子：
25
作者：
Hu, Xiangyou;Hicks, Caitlin W.;Yan, Riqiang
通讯作者：
Yan, Riqiang
DOI：
10.2174/157488907782411783
发表时间：
2007-11-01
期刊：
Recent patents on CNS drug discovery
影响因子：
--
作者：
Evin, Genevieve;Kenche, Vijaya B
通讯作者：
Kenche, Vijaya B
影响因子：
4.8
作者：
Chang, Wan-Pin;Downs, Deborah;Tang, Jordan
通讯作者：
Tang, Jordan
影响因子：
4.8
作者：
Dominguez, D;Tournoy, J;De Strooper, B
通讯作者：
De Strooper, B