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
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
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DOI：
10.2174/1567205013666161201201227
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发表时间：
2017-01-01
影响因子：
2.1
通讯作者：
Vogelgesang, Silke
中科院分区：
文献类型：
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作者：
Brueckmann, Sascha;Brenn, Anja;Vogelgesang, Silke
背景资料：针对β-淀粉样蛋白（A β）的免疫减少脑A β沉积并改善转基因小鼠模型中的认知能力，因此已被认为是阿尔茨海默病（AD）的有前景的疾病改善治疗方法。虽然在AD患者中的临床试验已经产生了清除实质A β斑块的证据，但治疗患者的血管中A β增加。我们推测，从大脑中清除A β的机制中与年龄相关的下降可能至少部分导致A β清除和重新分配失败。A β通过血脑屏障的排出是由专门的转运蛋白如P-糖蛋白介导的目的：探讨血脑屏障P-gp缺失对APP/PS1（+/-）P-gp ko小鼠A β肽免疫效果的影响。用人A β 42主动免疫雄性APP/PS1+/-P-gp wt（n = 8）和APP/PS1+/-P-gp ko（n = 8）小鼠。在行为测试后，在395天（+/-5天）龄时处死动物，并测量针对A β的抗体滴度。大脑被解剖和可溶性/不溶性大脑A β定量，另外的淀粉样斑块的数量和淀粉样血管病的严重程度进行了evaluated.Results：在免疫小鼠与完整的P-gp，我们的研究结果表明，可溶性和不溶性A β 40和A β 42显着减少。此外，免疫接种显著降低了A β斑块负荷。相比之下，缺乏功能性P-gp的免疫APP/PS1+/-P-gp ko小鼠未显示出A β 40或A β 42在脑中蓄积的减少，除了可溶形式的A β 42。此外，主动免疫后，这些小鼠表现出更强的脑内淀粉样血管病。结论：结果表明，缺乏P-gp的结果在一个显着的干扰A β从大脑中清除和增加脑实质内淀粉样血管病后，对A β免疫。我们的数据表明，选择性上调P-gp可以增强A β免疫治疗或预防AD的效果。
Background: Immunization against beta-amyloid (A beta) reduces cerebral A beta 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 A beta plaques, A beta increases in blood vessels of treated patients. We hypothesize that an age-related decline in the mechanisms that clear A beta from the brain might be at least in part responsible for the failure to purge and re-distribute A beta. The expulsion of A beta 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 blood-brain barrier on the effectiveness of A beta 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 A beta 42. After behavioral testing animals were sacrificed at the age of 395 days (+/- 5 days) and antibody titres against A beta were measured. Brains were dissected and soluble/insoluble cerebral A beta 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 A beta 40 and A beta 42. Furthermore, immunization significantly reduced A beta plaque burden. In contrast, immunized APP/PS1+/-P-gp ko mice lacking functional P-gp did not show a reduction of A beta 40 or A beta 42 accumulation in the brain except for the soluble form of A beta 42. 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 A beta removal from the brain and increased intraparenchymal cerebral amyloid angiopathy after immunization against A beta. Our data indicate that the selective up-regulation of P-gp could enhance the efficacy of A beta immunization in the treatment or prevention of AD.