Genetic reductions of beta-site amyloid precursor protein-cleaving enzyme 1 and amyloid-beta ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer's disease model mice.
Genetic reductions of beta-site amyloid precursor protein-cleaving enzyme 1 and amyloid-beta ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer's disease model mice.
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DOI：
10.1111/j.1460-9568.2009.07031.x
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Ohno M
中科院分区：
文献类型：
--
作者：
Devi L;Ohno M
虽然阿尔茨海默病（AD）转基因小鼠模型概括了淀粉样蛋白-β (Aβ)相关病理和认知障碍，但以往的研究主要是通过水迷宫和恐惧条件反射等行为任务来评估其海马依赖性记忆功能障碍。然而，随着疾病的发展，阿尔茨海默病的多个记忆系统会受损，因此测试其他形式的记忆是否在阿尔茨海默病模型中受到影响是很重要的。本研究旨在利用条件味觉厌恶（CTA）和情境恐惧条件反射范式，分别比较具有5个家族性AD （FAD）突变的5XFAD APP/PS1转基因小鼠海马独立和依赖记忆功能的表型。虽然5XFAD小鼠两种类型的记忆都明显受损，但CTA记忆缺陷（~9个月大）的发病时间比情境记忆缺陷（~6个月大）的发病时间要晚。此外，5XFAD小鼠通过基因工程降低了β位点app切割酶1 （BACE1+/−·5XFAD）的水平，表现出改善的CTA记忆，这与野生型对照组的表现相当。重要的是，在BACE1+/−·5XFAD小鼠中，5XFAD小鼠中升高的脑β-分泌酶裂解c -末端片段（C99）和a - β肽水平显著降低。此外，与5XFAD小鼠相比，BACE1+/−·5XFAD小鼠的岛叶皮质和杏仁核基底外侧的Aβ沉积也减少了，这两个大脑区域与CTA表现有关键关系。我们的研究结果表明，CTA模式可用于评估AD模型小鼠海马独立形式的记忆缺陷，该模型小鼠对β-分泌酶BACE1的部分减少和脑a β的部分减少很敏感。
Although transgenic mouse models of Alzheimer’s disease (AD) recapitulate amyloid-β (Aβ)-related pathologies and cognitive impairments, previous studies have mainly evaluated their hippocampus-dependent memory dysfunctions using behavioral tasks such as the water maze and fear conditioning. However, multiple memory systems become impaired in AD as disease progresses, and it is important to test whether other forms of memory are affected in AD models. This study was designed to use conditioned taste aversion (CTA) and contextual fear conditioning paradigms to compare the phenotypes of hippocampus-independent and dependent memory functions, respectively, in 5XFAD APP/PS1 transgenic mice that harbor five familial AD (FAD) mutations. While both types of memory were significantly impaired in 5XFAD mice, the onset of CTA memory deficits (~9 months of age) was delayed compared to that of contextual memory deficits (~6 months of age). Furthermore, 5XFAD mice genetically engineered to have reduced levels of β-site APP-cleaving enzyme 1 (BACE1+/−·5XFAD) exhibited improved CTA memory, which was equivalent to the performance of wild-type controls. Importantly, elevated levels of cerebral β-secretase-cleaved C-terminal fragment (C99) and Aβ peptides in 5XFAD mice were significantly reduced in BACE1+/−·5XFAD mice. Furthermore, Aβ deposition in the insular cortex and basolateral amygdala, two brain regions critically involved in CTA performance, was also reduced in BACE1+/−·5XFAD mice compared to 5XFAD mice. Our findings indicate that the CTA paradigm is useful for evaluating a hippocampus-independent form of memory defects in AD model mice, which is sensitive to rescue by partial reductions of the β-secretase BACE1 and consequently of cerebral Aβ.
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影响因子：
5.3
作者：
Laird, FM;Cai, HB;Wong, PC
通讯作者：
Wong, PC
DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart
影响因子：
--
作者：
Fukumoto, H;Cheung, BS;Irizarry, MC
通讯作者：
Irizarry, MC
影响因子：
11.2
作者：
Holsinger, RMD;McLean, CA;Evin, G
通讯作者：
Evin, G
影响因子：
13.6
作者：
LaFerla, FM;Oddo, S
通讯作者：
Oddo, S