Treatment with an amyloid-β antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer's disease
Treatment with an amyloid-β antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer's disease
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DOI：
10.1523/jneurosci.0664-05.2005
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发表时间：
2005-06-29
影响因子：
5.3
通讯作者：
Holtzman, DM
中科院分区：
文献类型：
--
作者：
Hartman, RE;Izumi, Y;Holtzman, DM
PDAPP转基因小鼠在CNS神经元中血小板衍生生长因子启动子的控制下过表达突变形式的人淀粉样前体蛋白，其导致人类早发性家族性阿尔茨海默病。这些具有混合遗传背景的小鼠已被证明从早期就有大量的学习障碍，以及学习能力的年龄依赖性下降，这被假设是由淀粉样蛋白β（A β）积累引起的。本研究的目的是确定：（1）纯C57 BL/6背景下的PDAPP小鼠是否比野生型小鼠出现更严重的年龄依赖性学习缺陷;（2）如果是，A β积累是否导致学习能力过度下降;（3）即使在显著的A β沉积后，学习缺陷是否可逆。在4-6、10-12或17-19月龄时，在5周水迷宫方案中测试C57 BL/6背景下的PDAPP和同窝野生型小鼠，其中逃逸平台的位置每周改变，要求小鼠重复学习新信息。PDAPP小鼠早在4个月时就表现出空间学习受损（前A β沉积），野生型和PDAPP小鼠的表现都随着年龄的增长而下降。然而，PDAPP小鼠随着年龄的增长表现出明显更大的恶化。观察到抗A β抗体10 D5持续数周的全身治疗减少了斑块沉积、增加了血浆A β、改善了海马长时程增强，并提供了A β积累在PDAPP小鼠年龄相关性恶化中作用的直接证据。改善了A β负荷较大的老年PDAPP小鼠的行为表现。
PDAPP transgenic mice overexpress a mutant form of human amyloid precursor protein under control of the platelet-derived growth factor promoter in CNS neurons that causes early onset, familial Alzheimer's disease in humans. These mice, on a mixed genetic background, have been shown to have substantial learning impairments from early ages, as well as an age-dependent decline in learning ability that has been hypothesized to be caused by amyloid-beta(A beta) accumulation. The goals of this study were to determine: (1) whether PDAPP mice on a pure C57BL/6 background develop more severe age-dependent learning deficits than wild-type mice; (2) if so, whether A beta accumulation accounts for the excessive decline in learning ability; and (3) whether the learning deficits are reversible, even after significant A beta deposition. At 4-6, 10-12, or 17-19 months of age, PDAPP and littermate wild-type mice on a C57BL/6 background were tested on a 5 week water maze protocol in which the location of the escape platform changed weekly, requiring the mice to repeatedly learn new information. PDAPP mice exhibited impaired spatial learning as early as 4 months (pre-A beta deposition), and the performance of both wild-type and PDAPP mice declined with age. However, PDAPP mice exhibited significantly greater deterioration with age. Direct evidence for the role of A beta accumulation in the age-related worsening in PDAPP mice was provided by the observation that systemic treatment over several weeks with the anti-A beta antibody 10D5 reduced plaque deposition, increased plasma A beta, improved hippocampal long-term potentiation, and improved behavioral performance in aged PDAPP mice with substantial A beta burden.