Transgenic Mice with Chronic NGF Deprivation and Alzheimer's Disease-Like Pathology Display Hippocampal Region-Specific Impairments in Short- and Long-Term Plasticities
Transgenic Mice with Chronic NGF Deprivation and Alzheimer's Disease-Like Pathology Display Hippocampal Region-Specific Impairments in Short- and Long-Term Plasticities
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DOI：
10.1523/jneurosci.0457-10.2010
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发表时间：
2010-09-29
影响因子：
5.3
通讯作者：
Marie, Helene
中科院分区：
文献类型：
--
作者：
Houeland, Gry;Romani, Armando;Marie, Helene
阿尔茨海默病(AD)的病因仍然难以捉摸。“淀粉样蛋白”假说认为，累积的β-淀粉样多肽(A-β)对突触功能的毒性作用会导致AD认知功能下降。这一假说得到了基于家族性AD(FAD)的转基因小鼠模型的分析支持，在该模型中，淀粉样前体蛋白(APP)的处理改变导致Aβ积累，与海马依赖的记忆缺陷相关。一些研究报道了这些小鼠齿状回(DG)谷氨酸能可塑性的显著变化，而CA1的可塑性相对不受影响。另一方面，“神经营养失衡”假说认为，AD相关的胆碱能信号丧失和APP处理改变是由于神经生长因子(NGF)营养支持的改变。这一假说得到了对AD11小鼠的分析支持，AD11小鼠在成年期表现出慢性NGF缺乏，并表现出类似AD的病理，包括Aβ积聚和海马区依赖的记忆缺陷。在这项研究中，我们分析了AD11小鼠的CA1和DG谷氨酸能可塑性，以评估这些小鼠是否也具有FAD模型，这是海马区突触功能障碍的常见表型。我们报告AD11小鼠表现出与年龄相关的短期和长期DG可塑性缺陷，而CA1可塑性相对较少。我们还报道，在较低的但生理的神经递质释放条件下，这两个结构都表现出增强的谷氨酸能传递，这一缺陷在进一步评估AD病理基础上的海马区突触缺陷时应该被考虑。我们的结论是，DG可塑性的严重缺陷是这两种病因上不同类型的AD小鼠模型之间的另一个共同点，与最初的损害(FAD突变的过度表达或NGF剥夺)无关。
The etiology of Alzheimer's disease (AD) remains elusive. The "amyloid" hypothesis states that toxic action of accumulated beta-amyloid peptide (A beta) on synaptic function causes AD cognitive decline. This hypothesis is supported by analysis of familial AD (FAD)-based transgenic mouse models, where altered amyloid precursor protein (APP) processing leads to A beta accumulation correlating with hippocampal-dependent memory deficits. Some studies report prominent dentate gyrus (DG) glutamatergic plasticity alterations in these mice, while CA1 plasticity remains relatively unaffected. The "neurotrophic unbalance" hypothesis, on the other hand, states that AD-related loss of cholinergic signaling and altered APP processing are due to alterations in nerve growth factor (NGF) trophic support. This hypothesis is supported by analysis of the AD11 mouse, which exhibits chronic NGF deprivation during adulthood and displays AD-like pathology, including A beta accumulation and hippocampal-dependent memory deficits. In this study, we analyzed CA1 and DG glutamatergic plasticity in AD11 mice to evaluate whether these mice also share with FAD models a common phenotype in hippocampal synaptic dysfunction. We report that AD11 mice display age-dependent short-and long-term DG plasticity deficits, while CA1 plasticity remains relatively spared. We also report that both structures exhibit enhanced glutamatergic transmission under lower, yet physiological, neurotransmitter release conditions, a defect that should be considered when further evaluating hippocampal synaptic deficits underlying AD pathology. We conclude that severe deficits in DG plasticity represent another common denominator between these two etiologically different types of AD mouse models, independent of the initial insult (overexpression of FAD mutation or NGF deprivation).