Mizukami Katsuyoshi, Akatsu Hiroyasu, Abrahamson Eric E, Mi Zhiping, Ikonomovic Milos D
Faculty of Health and Sport Sciences, Tsukuba, Japan.
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Neuropathology. 2016 Apr;36(2):135-45. doi: 10.1111/neup.12241. Epub 2015 Aug 21.
Studies of acetylcholine degrading enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in Alzheimer's disease (AD) have suggested their potential role in the development of fibrillar amyloid-β (Aβ) plaques (amyloid plaques). A recent genome-wide association study analysis identified a novel association between genetic variations in the BCHE locus and amyloid burden. We studied BChE immunoreactivity in hippocampal tissue sections from AD and control cases, and examined its relationship with amyloid plaques, neurofibrillary tangles (NFT), dystrophic neurites (DN) and neuropil threads (NT). Compared to controls, AD cases had greater BChE immunoreactivity in hippocampal neurons and neuropils in CA2/3, but not in the CA1, CA4 and dentate gyrus. The majority of amyloid plaques (> 80%, using a pan-amyloid marker X-34) contained discrete neuritic clusters which were dual-labeled with antibodies against BChE and phosphorylated tau (clone AT8). There was no association between overall regional BChE immunoreaction intensity and amyloid plaque burden. In contrast to previous reports, BChE was localized in only a fraction (~10%) of classic NFT (positive for X-34). A similar proportion of BChE-immunoreactive pyramidal cells were AT8 immunoreactive. Greater NFT and DN loads were associated with greater BChE immunoreaction intensity in CA2/3, but not in CA1, CA4 and dentate gyrus. Our results demonstrate that in AD hippocampus, BChE accumulates in neurons and plaque-associated neuritic clusters, but only in a small proportion of NFT. The association between greater neurofibrillary pathology burden and markedly increased BChE immunoreactivity, observed selectively in CA2/3 region, could reflect a novel compensatory mechanism. Since CA2/3 is generally considered more resistant to AD pathology, BChE upregulation could impact the cholinergic modulation of glutamate neurotransmission to prevent/reduce neuronal excitotoxicity in AD hippocampus.
对阿尔茨海默病（AD）中乙酰胆碱降解酶乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的研究表明，它们在纤维状淀粉样β蛋白（Aβ）斑块（淀粉样斑块）形成过程中可能发挥作用。最近一项全基因组关联研究分析确定了BCHE基因座的基因变异与淀粉样蛋白负荷之间存在新的关联。我们研究了AD病例和对照病例海马组织切片中的BChE免疫反应性，并检测了其与淀粉样斑块、神经原纤维缠结（NFT）、营养不良性神经突（DN）和神经毡丝（NT）的关系。与对照组相比，AD病例在CA2/3区的海马神经元和神经毡中BChE免疫反应性更强，但在CA1、CA4和齿状回中则不然。大多数淀粉样斑块（使用泛淀粉样标志物X-34检测，>80%）包含离散的神经突簇，这些神经突簇用抗BChE和磷酸化tau（克隆AT8）抗体进行双重标记。区域总体BChE免疫反应强度与淀粉样斑块负荷之间没有关联。与之前的报道不同, BChE仅定位于一小部分（约10%）经典NFT（X-34阳性）中。类似比例的BChE免疫反应性锥体细胞为AT8免疫反应阳性。CA2/3区中更大的NFT和DN负荷与更强的BChE免疫反应强度相关，但在CA1、CA4和齿状回中则不然。我们的结果表明，在AD海马中，BChE在神经元和斑块相关的神经突簇中积累，但仅在一小部分NFT中存在。在CA2/3区选择性观察到的更大神经原纤维病理负担与明显增加的BChE免疫反应性之间的关联，可能反映了一种新的代偿机制。由于CA2/3区通常被认为对AD病理更具抵抗力，BChE上调可能会影响谷氨酸神经传递的胆碱能调节，以预防/减少AD海马中的神经元兴奋性毒性。
