Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses.
Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses.
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阿尔茨海默病相关的淀粉样蛋白-β和淀粉样蛋白-β蛋白前体与突触的异质关联。
DOI：
10.3233/jad-170262
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Gouras GK
中科院分区：
文献类型：
--
作者：
Willén K;Sroka A;Takahashi RH;Gouras GK
阿尔茨海默病(AD)越来越被认为是一种突触疾病。与阿尔茨海默病的标志性神经病理损害--淀粉样斑块和神经原纤维缠结相比，突触丢失与认知能力下降的相关性更好。可溶性淀粉样蛋白-β(A-β)是突触功能障碍的调节因子。β结合、积累和聚集在突触上。然而，Aβ和A-β蛋白前体(A-βPP)在AD中的解剖学和神经递质特异性仍然知之甚少。此外，Aβ和AβPP在AD发生发展中的相对作用尚不清楚，分别位于突触前和突触后以及轴突和树突。在这里，我们使用免疫金电子显微镜和共聚焦显微镜为Aβ/AβPP定位的异质性提供证据。我们证明了Aβ与培养神经元中突触的一个子集结合，与GABA能神经元相比，与谷氨酸能神经元的结合更优先。我们还强调了通过共聚焦显微镜定义这种结合的突触前和突触后定位的挑战。此外，内源性Aβ42在谷氨酸能和GABA能AβPP/PS1转基因原代神经元中均有积累，但水平不同。此外，在敲除早老素1或抑制γ-分泌酶A时，βPP C末端片段在突触前和突触后积聚；但在突触前较早，与AβPP在轴突中的较高处理速度一致。更好地了解Aβ/AβPP在AD中的突触和解剖选择性，对于开发更有效的新疗法来治疗这一主要的衰老疾病具有重要意义。
Alzheimer’s disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-β (Aβ) have emerged as mediators of synapse dysfunction. Aβ binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aβ and the amyloid-β protein precursor (AβPP) in AD remain poorly understood. In addition, the relative roles of Aβ and AβPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Aβ/AβPP. We demonstrate that Aβ binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Aβ42 accumulates in both glutamatergic and GABAergic AβPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of γ-secretase AβPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AβPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Aβ/AβPP in AD can be important for the development of more effective new therapies for this major disease of aging.