Wilhelmus Micha M M, Otte-Höller Irene, van Triel Jos J J, Veerhuis Robert, Maat-Schieman Marion L C, Bu Guojun, de Waal Robert M W, Verbeek Marcel M
Department of Neurology and Alzheimer Center, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Am J Pathol. 2007 Dec;171(6):1989-99. doi: 10.2353/ajpath.2007.070050. Epub 2007 Nov 30.
Inefficient clearance of A beta, caused by impaired blood-brain barrier crossing into the circulation, seems to be a major cause of A beta accumulation in the brain of late-onset Alzheimer's disease patients and hereditary cerebral hemorrhage with amyloidosis Dutch type. We observed association of receptor for advanced glycation end products, CD36, and low-density lipoprotein receptor (LDLR) with cerebral amyloid angiopathy in both Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis Dutch type brains and increased low-density lipoprotein receptor-related protein-1 (LRP-1) expression by perivascular cells in cerebral amyloid angiopathy. We investigated if these A beta receptors are involved in A beta internalization and in A beta-mediated cell death of human cerebrovascular cells and astrocytes. Expression of both the LRP-1 and LDLR by human brain pericytes and leptomeningeal smooth muscle cells, but not by astrocytes, increased on incubation with A beta. Receptor-associated protein specifically inhibited A beta-mediated up-regulation of LRP-1, but not of LDLR, and receptor-associated protein also decreased A beta internalization and A beta-mediated cell death. We conclude that especially LRP-1 and, to a minor extent, LDLR are involved in A beta internalization by and A beta-mediated cell death of cerebral perivascular cells. Although perivascular cells may adapt their A beta internalization capacity to the levels of A beta present, saturated LRP-1/LDLR-mediated uptake of A beta results in degeneration of perivascular cells.
由于血脑屏障进入循环系统受损导致的β淀粉样蛋白（Aβ）清除效率低下，似乎是晚发型阿尔茨海默病患者和荷兰型淀粉样变性遗传性脑出血患者脑内Aβ积累的主要原因。我们观察到晚期糖基化终末产物受体、CD36和低密度脂蛋白受体（LDLR）与阿尔茨海默病和荷兰型淀粉样变性遗传性脑出血患者脑内的脑淀粉样血管病相关，并且脑淀粉样血管病中血管周围细胞的低密度脂蛋白受体相关蛋白1（LRP-1）表达增加。我们研究了这些Aβ受体是否参与人脑血管细胞和星形胶质细胞的Aβ内化以及Aβ介导的细胞死亡。人脑海绵状血管周细胞和软脑膜平滑肌细胞而非星形胶质细胞在与Aβ孵育后，LRP-1和LDLR的表达均增加。受体相关蛋白特异性抑制Aβ介导的LRP-1上调，但不抑制LDLR上调，并且受体相关蛋白也减少Aβ内化和Aβ介导的细胞死亡。我们得出结论，尤其是LRP-1，以及在较小程度上的LDLR，参与了脑血管周围细胞的Aβ内化和Aβ介导的细胞死亡。尽管血管周围细胞可能使其Aβ内化能力适应所存在的Aβ水平，但饱和的LRP-1/LDLR介导的Aβ摄取会导致血管周围细胞变性。
