The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM.
The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM.
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DOI：
10.1016/j.bbi.2018.07.017
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Pietrzik CU
中科院分区：
文献类型：
--
作者：
Storck SE;Hartz AMS;Bernard J;Wolf A;Kachlmeier A;Mahringer A;Weggen S;Pahnke J;Pietrzik CU
神经毒性淀粉样蛋白-β（Aβ）在脑中的积累是阿尔茨海默病（AD）的特征性标志。血脑屏障（BBB）提供了一个大的表面积，并已被证明是脑Aβ清除的重要介质。ABC转运蛋白P-gp（ABCB 1/P-gp）和受体低密度脂蛋白受体相关蛋白1（LRP 1）在Aβ流出脑中起重要作用。在这里，通过免疫沉淀实验、共免疫染色和ABCB 1/P-gp和LRP 1的双重抑制，我们表明这两种蛋白质在功能上是相连的，介导Aβ通过内皮细胞的协同转胞吞作用。迟发型AD风险因子磷脂酰肌醇结合网格蛋白组装蛋白（PICALM）与ABCB 1/P-gp和LRP 1相关，代表功能性连接并引导两种蛋白质通过脑内皮。总之，我们的研究结果提供了关于Aβ穿过BBB转运的更多机制见解，并表明不同清除蛋白的功能相互作用是从大脑中快速清除Aβ所必需的。
The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic hallmark of Alzheimer’s disease (AD). The blood-brain barrier (BBB) provides a large surface area and has been shown to be an important mediator for removal of brain Aβ. Both, the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low-density lipoprotein receptor-related protein 1 (LRP1) have been implicated to play crucial roles in Aβ efflux from brain. Here, with immunoprecipitation experiments, co-immunostainings and dual inhibition of ABCB1/P-gp and LRP1, we show that both proteins are functionally linked, mediating a concerted transcytosis of Aβ through endothelial cells. Late-onset AD risk factor Phosphatidylinositol binding clathrin assembly protein (PICALM) is associated with both ABCB1/P-gp and LRP1 representing a functional link and guiding both proteins through the brain endothelium. Together, our results give more mechanistic insight on Aβ transport across the BBB and show that the functional interplay of different clearance proteins is needed for the rapid removal of Aβ from the brain.
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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：
4.6
作者：
Dodacki A;Wortman M;Saubaméa B;Chasseigneaux S;Nicolic S;Prince N;Lochus M;Raveu AL;Declèves X;Scherrmann JM;Patel SB;Bourasset F
通讯作者：
Bourasset F
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
4
作者：
Do, Tuan Minh;Noel-Hudson, Marie-Sophie;Bourasset, Fanchon
通讯作者：
Bourasset, Fanchon
影响因子：
4.2
作者：
Lambert, Jean-Charles;Zelenika, Diana;Amouyel, Philippe
通讯作者：
Amouyel, Philippe