Cui Youhong, Le Yingying, Yazawa Hiroshi, Gong Wanghua, Wang Ji Ming
Biochemistry Section, Lanzhou Military Medical University, Lanzhou, People's Republic of China.
J Leukoc Biol. 2002 Oct;72(4):628-35.
Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by the presence of multiple senile plaques in the brain tissue, which are also associated with considerable inflammatory infiltrates. Although the precise mechanisms of the pathogenesis of AD remain to be determined, the overproduction and precipitation of a 42 amino acid form of beta amyloid (Abeta(42)) in plaques have implicated Abeta in neurodegeneration and proinflammatory responses seen in the AD brain. Our recent studies revealed that the activation of formyl peptide receptor-like 1 (FPRL1), a seven-transmembrane, G-protein-coupled receptor, by Abeta(42) may be responsible for accumulation and activation of mononuclear phagocytes (monocytes and microglia). We further found that upon binding FPRL1, Abeta(42) was rapidly internalized into the cytoplasmic compartment in the form of Abeta(42)/FPRL1 complexes. Persistent exposure of FPRL1-expressing cells to Abeta(42) resulted in intracellular retention of Abeta(42)/FPRL1 complexes and the formation of Congo-red-positive fibrils in mononuclear phagocytes. Our observations suggest that FPRL1 may not only mediate the proinflammatory activity of Abeta(42) but also actively participate in Abeta(42) uptake and the resultant fibrillar formation. Therefore, FPRL1 may constitute an additional molecular target for the development of therapeutic agents for AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是脑组织中存在多个老年斑，这些老年斑还伴有大量炎性浸润。尽管AD发病机制的确切机制仍有待确定，但斑块中42个氨基酸形式的β淀粉样蛋白（Abeta(42)）的过量产生和沉淀已表明Abeta与AD脑中的神经退行性变和促炎反应有关。我们最近的研究表明，Abeta(42)激活七跨膜G蛋白偶联受体——类甲酰肽受体1（FPRL1），可能是单核吞噬细胞（单核细胞和小胶质细胞）聚集和激活的原因。我们进一步发现，Abeta(42)与FPRL1结合后，会以Abeta(42)/FPRL1复合物的形式迅速内化到细胞质区室。持续将表达FPRL1的细胞暴露于Abeta(42)会导致Abeta(42)/FPRL1复合物在细胞内滞留，并在单核吞噬细胞中形成刚果红阳性纤维。我们的观察结果表明，FPRL1不仅可能介导Abeta(42)的促炎活性，还可能积极参与Abeta(42)的摄取以及由此产生的纤维形成。因此，FPRL1可能构成AD治疗药物开发的另一个分子靶点。
