摘要
背景:对β淀粉样蛋白(Aβ)的免疫降低了脑β-沉积,并提高了转基因小鼠模型的认知能力,因此被认为是阿尔茨海默病(AD)的一种很有前途的疾病修饰治疗方法。虽然AD患者的临床试验已经取得了实质性Aβ斑块清除的证据,但治疗组患者的血管β增加。我们推测,与年龄有关的机制,清除一个β从大脑可能至少部分负责清除和重新分发β。通过血脑屏障的β除名是由专门的转运蛋白,如P-糖蛋白(P-gp介导,ABCB1/MD 目的:本研究的目的是调查的影响,缺乏P-gp在血脑屏障的有效性的一个β肽免疫APP/PS1 + / -糖蛋白基因敲除小鼠 方法:雄性APP/PS1±P-gp WT(n = 8)和APP/PS1±P-gp KO(n = 8)小鼠进行主动免疫β42人。行为测试后,动物均在395日龄处死(+ / - 5天),对β抗体滴度的测定。大脑进行解剖和溶/不溶性脑β量化,此外,淀粉样血管病的淀粉样斑块的数量和严重程度进行评估 结果:在完整的P-gp免疫小鼠中,我们的研究结果显示可溶性和不溶性β40和β1显著降低。此外,免疫显著降低了β斑块的负担。相反,免疫APP/PS1 + / -糖蛋白基因敲除小鼠缺乏功能P-gp并未减少一个β40或42β积累在大脑以外的可溶性形式的一个β42。此外,在主动免疫小鼠显示出较强的脑淀粉样血管 结论:结果表明,在β免疫后P-gp结果从大脑β去除明显没有干扰和增加脑内淀粉样脑血管病。我们的数据表明,选择性上调P-糖蛋白可以提高疗效的β免疫治疗或预防AD
关键词: 主动免疫,阿尔茨海默病,淀粉样血管病,β-淀粉样蛋白,血脑屏障,间隙,Pglycoprotein。
Current Alzheimer Research
Title:Lack of P-glycoprotein Results in Impairment of Removal of Beta-Amyloid and Increased Intraparenchymal Cerebral Amyloid Angiopathy after Active Immunization in a Transgenic Mouse Model of Alzheimer's Disease
Volume: 14 Issue: 6
关键词: 主动免疫,阿尔茨海默病,淀粉样血管病,β-淀粉样蛋白,血脑屏障,间隙,Pglycoprotein。
摘要: Background: Immunization against beta-amyloid (Aβ) reduces cerebral Aβ deposits and improves cognitive capacities in transgenic mouse models, and thus has been considered a promising disease- modifying therapeutic approach for Alzheimer’s disease (AD). Although clinical trials in AD patients have yielded evidence for clearance of parenchymal Aβ plaques, Aβ increases in blood vessels of treated patients. We hypothesize that an age-related decline in the mechanisms that clear Aβ from the brain might be at least in part responsible for the failure to purge and re-distribute Aβ. The expulsion of Aβ via the blood-brain barrier is mediated by specialized transport proteins such as P-glycoprotein (P-gp, ABCB1/MDR1).
Objective: The objective of this study is to investigate the influence of the absence of P-gp at the bloodbrain barrier on the effectiveness of Aβ peptide immunization in APP/PS1+/- P-gp ko mice. Methods: Male APP/PS1+/- P-gp wt (n = 8) and APP/PS1+/- P-gp ko (n = 8) mice were actively immunized with human Aβ42. After behavioral testing animals were sacrificed at the age of 395 days (+/- 5 days) and antibody titres against Aβ were measured. Brains were dissected and soluble/insoluble cerebral Aβ was quantified, additionally the number of amyloid plaques and severity of amyloid angiopathy were evaluated. Results: In immunized mice with intact P-gp, our results showed a significant reduction of soluble and insoluble Aβ40 and Aβ42. Furthermore, immunization significantly reduced Aβ plaque burden. In contrast, immunized APP/PS1+/- P-gp ko mice lacking functional P-gp did not show a reduction of Aβ40 or Aβ42 accumulation in the brain except for the soluble form of Aβ42. Furthermore, after active immunization these mice displayed a stronger intracerebral amyloid angiopathy. Conclusion: The results show that the absence of P-gp results in a significant disturbance of Aβ removal from the brain and increased intraparenchymal cerebral amyloid angiopathy after immunization against Aβ. Our data indicate that the selective up-regulation of P-gp could enhance the efficacy of Aβ immunization in the treatment or prevention of AD.Export Options
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Cite this article as:
Lack of P-glycoprotein Results in Impairment of Removal of Beta-Amyloid and Increased Intraparenchymal Cerebral Amyloid Angiopathy after Active Immunization in a Transgenic Mouse Model of Alzheimer's Disease, Current Alzheimer Research 2017; 14 (6) . https://dx.doi.org/10.2174/1567205013666161201201227
DOI https://dx.doi.org/10.2174/1567205013666161201201227 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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