Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models
Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models
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DOI：
10.1073/pnas.96.6.3228
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发表时间：
1999-03-16
影响因子：
11.1
通讯作者：
Mucke, L
中科院分区：
文献类型：
--
作者：
Hsia, AY;Masliah, E;Mucke, L
常染色体显性形式的家族性阿尔茨海默病(FAD)与淀粉样β蛋白前体(APP)衍生的淀粉样β多肽Aβ42的产生增加有关，在FAD中，就像在散发性形式的疾病中一样，Aβ多肽异常积累。在大脑中以淀粉样斑块的形式，他在这里展示了在转基因小鼠的神经元中过表达FAD(717(V->；F))-突变的人APP降低了突触前终末和神经元的密度，这些小鼠在形成淀粉样斑块之前就死了。来自海马体的电生理记录显示，突触传递存在明显的缺陷，这也比淀粉样蛋白沉积早了几个月。虽然在幼龄小鼠中，功能和结构神经元的缺陷程度相似，但随着年龄的增长，功能缺陷变得突出。通过在第二系小鼠的APP转基因中添加瑞典FAD突变而实现的总体APP表达下降的竞争中，Aβ产量增加，进一步增加了没有斑块的年轻APP小鼠的突触传递缺陷。这些结果表明，Aβ具有独立于斑块形成的神经毒性作用。
Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid beta peptide, A beta 42, which is derived from the amyloid protein precursor (APP), In FAD, as Hell as in sporadic forms of the illness, A beta peptides accumulate abnormally. in the brain in the form of amyloid plaques, Here, He show that overexpression of FAD(717(V-->F))-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons Hell before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits Here of similar magnitude, functional deficits became predominant with advancing age. Increased A beta production in the contest of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of A beta that is independent of plaque formation.