DeBay Drew R, Reid George A, Macdonald Ian R, Mawko George, Burrell Steve, Martin Earl, Bowen Chris V, Darvesh Sultan
Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada; Biomedical Translational Imaging Centre, Halifax, Nova Scotia, Canada.
Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
Brain Res. 2017 Sep 15;1671:102-110. doi: 10.1016/j.brainres.2017.07.009. Epub 2017 Jul 17.
Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of β-amyloid (Aβ) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with Aβ pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing Aβ plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar Aβ than 5XFAD mice at the same age. Therefore, BChE may have a role in Aβ pathogenesis. Furthermore, in AD, diminished glucose metabolism in the brain can be detected in vivo with positron emission tomography (PET) imaging following 2-deoxy-2-(F)fluoro-D-glucose (FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar Aβ burden, whole brain and regional uptake of FDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WT and WT) strains at 5months. Diminished fibrillar Aβ burden was confirmed in 5XFAD/BChE-KO mice relative to 5XFAD. 5XFAD and 5XFAD/BChE-KO mice demonstrated reduction in whole brain FDG retention compared to respective wild-types. Regional analysis of relevant AD structures revealed reduction in FDG retention in 5XFAD mice in all brain regions analyzed (save cerebellum) compared to WT. Alternatively, 5XFAD/BChE-KO mice demonstrated a more selective pattern of reduced retention in the cerebral cortex and thalamus compared to WT, while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar Aβ, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice.
阿尔茨海默病（AD）是导致痴呆的最常见神经退行性疾病。AD大脑的一个标志是β-淀粉样蛋白（Aβ）斑块的沉积。AD也是一种胆碱能功能障碍状态，丁酰胆碱酯酶（BChE）与Aβ病理学相关。转基因小鼠（5XFAD）是一种侵袭性淀粉样变性模型，会产生Aβ斑块，BChE也与之相关。一种衍生品系（5XFAD/BChE-KO），其BChE基因被敲除，在相同年龄时，其纤维状Aβ水平显著低于5XFAD小鼠。因此，BChE可能在Aβ发病机制中起作用。此外，在AD中，给予2-脱氧-2-（F）氟-D-葡萄糖（FDG）后，可通过正电子发射断层扫描（PET）成像在体内检测到大脑葡萄糖代谢降低。为了确定代谢减退是否与BChE诱导的纤维状Aβ负荷变化有关，比较了5个月大时野生型（WT和WT）、5XFAD和5XFAD/BChE-KO小鼠全脑和局部FDG摄取情况。相对于5XFAD，5XFAD/BChE-KO小鼠的纤维状Aβ负荷降低得到证实。与各自野生型相比，5XFAD和5XFAD/BChE-KO小鼠全脑FDG滞留均减少。对相关AD结构的区域分析显示，与野生型相比，5XFAD小鼠所有分析脑区（小脑除外）的FDG滞留均减少。相比之下，与野生型相比，5XFAD/BChE-KO小鼠大脑皮层和丘脑的滞留减少模式更具选择性，而海马结构、杏仁核和基底神经节的滞留保持不变。这表明，敲除BChE并减少纤维状Aβ后，5XFAD/BChE-KO小鼠的许多结构可能对脑功能具有潜在保护作用。
