Protecting P-glycoprotein at the blood-brain barrier from degradation in an Alzheimer's disease mouse model.
Protecting P-glycoprotein at the blood-brain barrier from degradation in an Alzheimer's disease mouse model.
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DOI：
10.1186/s12987-021-00245-4
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发表时间：
2021-03-06
影响因子：
7.3
通讯作者：
Hartz AMS
中科院分区：
文献类型：
--
作者：
Ding Y;Zhong Y;Baldeshwiler A;Abner EL;Bauer B;Hartz AMS
未能从大脑中清除Aβ是阿尔茨海默病(AD)中Aβ脑积聚的部分原因。外排转运蛋白P-糖蛋白(P-β)是清除A蛋白通过血脑屏障的关键蛋白。在AD中，P-gp水平降低，这有助于Aβ脑清除受损。然而，导致P-gp水平下降的机制尚不清楚，也没有可用的策略来保护P-gp。我们以前在体外分离的脑毛细血管中证明了人Aβ40(HAβ40)通过激活泛素-蛋白酶体途径来触发P-gp的降解。在这个途径中，HAβ40启动P-gp泛素化，导致P-gp内化和蛋白酶体降解，从而导致P-gp蛋白表达和转运活性水平降低。在这里，我们扩展了这一研究路线，并展示了使用AD转基因小鼠模型(人类淀粉样前体蛋白(HAPP)过表达的小鼠；Tg2576)进行的体内研究的结果。在我们的研究中，HAPP小鼠被用赋形剂、诺可达唑(Ncz，阻断P-gp内化的微管抑制剂)或Ncz和P-gp抑制剂环孢素A(CsA)的联合治疗。我们测定了分离的小鼠脑毛细血管中P-gp蛋白的表达和转运活性水平，以及血浆和脑组织中的Aβ水平。用5 mg/kg NCZ连续14天治疗HAPP小鼠，可将P-gp水平提高到WT小鼠的水平。与此一致的是，与未治疗的HAPP小鼠相比，接受NCZ治疗的HAPP小鼠脑毛细血管中P-gp介导的HAβ42转运增加。重要的是，NCZ治疗显著降低了HAPP小鼠脑内HAβ40和HAβ42的水平，而血浆中HAβ40和HAβ42的水平保持不变。这些发现提供了体内证据，表明微管抑制维持P-gp蛋白表达和运输活性水平，这反过来有助于降低HAPP小鼠的HAβ脑水平。因此，在血脑屏障保护P-gp可能为AD和其他基于A-β的病理提供一种新的治疗策略。
Failure to clear Aβ from the brain is partly responsible for Aβ brain accumulation in Alzheimer’s disease (AD). A critical protein for clearing Aβ across the blood-brain barrier is the efflux transporter P-glycoprotein (P-gp). In AD, P-gp levels are reduced, which contributes to impaired Aβ brain clearance. However, the mechanism responsible for decreased P-gp levels is poorly understood and there are no strategies available to protect P-gp. We previously demonstrated in isolated brain capillaries ex vivo that human Aβ40 (hAβ40) triggers P-gp degradation by activating the ubiquitin-proteasome pathway. In this pathway, hAβ40 initiates P-gp ubiquitination, leading to internalization and proteasomal degradation of P-gp, which then results in decreased P-gp protein expression and transport activity levels. Here, we extend this line of research and present results from an in vivo study using a transgenic mouse model of AD (human amyloid precursor protein (hAPP)-overexpressing mice; Tg2576). In our study, hAPP mice were treated with vehicle, nocodazole (NCZ, microtubule inhibitor to block P-gp internalization), or a combination of NCZ and the P-gp inhibitor cyclosporin A (CSA). We determined P-gp protein expression and transport activity levels in isolated mouse brain capillaries and Aβ levels in plasma and brain tissue. Treating hAPP mice with 5 mg/kg NCZ for 14 days increased P-gp levels to levels found in WT mice. Consistent with this, P-gp-mediated hAβ42 transport in brain capillaries was increased in NCZ-treated hAPP mice compared to untreated hAPP mice. Importantly, NCZ treatment significantly lowered hAβ40 and hAβ42 brain levels in hAPP mice, whereas hAβ40 and hAβ42 levels in plasma remained unchanged. These findings provide in vivo evidence that microtubule inhibition maintains P-gp protein expression and transport activity levels, which in turn helps to lower hAβ brain levels in hAPP mice. Thus, protecting P-gp at the blood-brain barrier may provide a novel therapeutic strategy for AD and other Aβ-based pathologies.
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影响因子：
2.1
作者：
Brueckmann, Sascha;Brenn, Anja;Vogelgesang, Silke
通讯作者：
Vogelgesang, Silke
影响因子：
4.9
作者：
Hartz AM;Pekcec A;Soldner EL;Zhong Y;Schlichtiger J;Bauer B
通讯作者：
Bauer B
影响因子：
8.3
作者：
Hartz AM;Bauer B;Soldner EL;Wolf A;Boy S;Backhaus R;Mihaljevic I;Bogdahn U;Klünemann HH;Schuierer G;Schlachetzki F
通讯作者：
Schlachetzki F
影响因子：
2.1
作者：
Kuhn, M
通讯作者：
Kuhn, M
影响因子：
6.3
作者：
Hawkins, Brian T.;Rigor, Robert R.;Miller, David S.
通讯作者：
Miller, David S.