Nakamura Kenji, Ohya Wakana, Funakoshi Hiroshi, Sakaguchi Gaku, Kato Akira, Takeda Masatoshi, Kudo Takashi, Nakamura Toshikazu
Department of Biochemistry andMolecular Biology, Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
J Neurosci Res. 2006 Sep;84(4):874-90. doi: 10.1002/jnr.20992.
Accumulation of beta-amyloid protein (Abeta) in the brain is a hallmark of Alzheimer's disease (AD), and Abeta-mediated pathogenesis could result from increased production of Abeta or insufficient Abeta clearance by microglia, astrocytes, or the vascular system. Cell-surface receptors, such as scavenger receptors, might play a critical role in the binding and clearing of Abeta; however, the responsible receptors have yet to be identified. We show that scavenger receptor with C-type lectin (SRCL), a member of the scavenger receptor family containing coiled-coil, collagen-like, and C-type lectin/carbohydrate recognition domains, is expressed in cultured astrocytes and microglia. In contrast to the low expression of SRCL in the wild-type mouse brain, in a double transgenic mouse model of AD (Tg-APP/PS1), immunohistochemistry showed that SRCL was markedly induced in Abeta-positive astrocytes and Abeta-positive vascular/perivascular cells, which are associated closely with cerebral amyloid angiopathy. In patients with AD, the distribution of SRCL was similar to that seen in the Tg-APP/PS1 temporal cortex. The presence of a large number of SRCL/Abeta double-positive particles in the intracellular compartments of reactive astrocytes and vascular/perivascular cells in Tg-APP/PS1 mice and AD patients suggests a role for SRCL in Abeta clearance. Moreover, CHO-K1 cells transfected with SRCL isoforms were found to bind fibrillar Abeta(1-42). These findings suggest that SRCL could be the receptor involved in the binding or clearing of Abeta by glial and vascular/perivascular cells in AD.
β-淀粉样蛋白（Aβ）在大脑中的积累是阿尔茨海默病（AD）的一个标志，Aβ介导的发病机制可能是由于Aβ产生增加或小胶质细胞、星形胶质细胞或血管系统对Aβ清除不足所致。细胞表面受体，如清道夫受体，可能在Aβ的结合和清除中起关键作用；然而，相关受体尚未确定。我们发现，含有卷曲螺旋、胶原样和C型凝集素/碳水化合物识别结构域的清道夫受体家族成员——C型凝集素清道夫受体（SRCL），在培养的星形胶质细胞和小胶质细胞中表达。与野生型小鼠大脑中SRCL的低表达相反，在AD双转基因小鼠模型（Tg-APP/PS1）中，免疫组织化学显示，SRCL在Aβ阳性星形胶质细胞和Aβ阳性血管/血管周围细胞中显著诱导，这些细胞与脑淀粉样血管病密切相关。在AD患者中，SRCL的分布与Tg-APP/PS1颞叶皮质中的分布相似。在Tg-APP/PS1小鼠和AD患者的反应性星形胶质细胞以及血管/血管周围细胞的细胞内区室中存在大量SRCL/Aβ双阳性颗粒，这表明SRCL在Aβ清除中发挥作用。此外，发现转染了SRCL亚型的CHO-K1细胞能够结合纤维状Aβ（1-42）。这些发现表明，SRCL可能是AD中胶质细胞和血管/血管周围细胞参与Aβ结合或清除的受体。
