The amyloid pathology progresses in a neurotransmitter-specific manner
The amyloid pathology progresses in a neurotransmitter-specific manner
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DOI：
10.1016/j.neurobiolaging.2005.09.034
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发表时间：
2006-11-01
影响因子：
4.2
通讯作者：
Cuello, A. Claudio
中科院分区：
文献类型：
--
作者：
Bell, Karen F. S.;Ducatenzeiler, Adriana;Cuello, A. Claudio
过去使用早期淀粉样蛋白病理转基因模型的研究表明，淀粉样蛋白病理以一种神经递质特异性的方式进展，其中胆碱能终末最脆弱，其次是谷氨酸能终末，最后是更具抵抗力的GABA能终末。为了确定这种神经递质特异性的进展是否在以后的病理阶段持续，对18月龄的APP(K670N，M671L)+PS1(M146L)双转基因小鼠的突触前突起密度以及邻近营养不良突起的斑块的面积和定位进行了量化。定量分析表明，转基因动物突触前突触前区胆碱、谷氨酸和GABA能密度显著降低。胆碱能和谷氨酸能营养不良轴突似乎受到纤维蛋白Aβ的严重影响，因为随着斑块大小的增加，这两种类型的神经突起所占的面积都在减少。此外，胆碱能营养不良轴突比谷氨酸能营养不良轴突更接近斑块，而GABA能营养不良轴突无论斑块大小都很小。为了研究人类AD病理是否存在相似性，研制了一种抗人囊泡谷氨酸转运蛋白1(VG1uT1)的单抗(McKA1)。随后在AD脑组织中的染色显示了新的谷氨酸能营养不良神经突起的存在，据我们所知，这是AD病理中结构性谷氨酸能缺陷的第一个证据。(C)2005 Elsevier Inc.保留所有权利。
Past studies using transgenic models of early-staged amyloid pathology, have suggested that the amyloid pathology progresses in a neurotransmitter-specific manner where cholinergic terminals appear most vulnerable, followed by glutamatergic terminals and finally by somewhat more resistant GABAergic terminals. To determine whether this neurotransmitter-specific progression persists at later pathological stages, presynaptic bouton densities, and the areas of occupation and localization of plaque adjacent dystrophic neurites were quantified in 18-month-old APP(K670N,M671L)+PS1(M146L) doubly transgenic mice. Quantification revealed that transgenic animals had significantly lower cholinergic, glutamatergic and GABAergic presynaptic bouton densities. Cholinergic and glutamatergic dystrophic neurites appear to be heavily influenced by fibrillar A beta as both types displayed a decreasing area of occupation with respect to increasing plaque size. Furthermore, cholinergic dystrophic neurites reside in closer proximity to plaques than glutamatergic dystrophic neurites, while GABAergic dystrophic neurites were minimal regardless of plaque size. To investigate whether similarities exist in the human AD pathology, a monoclonal antibody (McKA1) against the human vesicular glutamate transporter 1 (VG1uT1) was developed. Subsequent staining in AD brain tissue revealed the novel presence of glutamatergic dystrophic neurites, to our knowledge the first evidence of a structural glutamatergic deficit in the AD pathology. (c) 2005 Elsevier Inc. All rights reserved.