Caillé Isabelle, Allinquant Bernadette, Dupont Edmond, Bouillot Colette, Langer Andreas, Müller Ulrike, Prochiantz Alain
CNRS UMR 8542, Ecole Normale Supérieure, 46 rue d'Ulm, 75005 Paris, France.
Development. 2004 May;131(9):2173-81. doi: 10.1242/dev.01103. Epub 2004 Apr 8.
The amyloid precursor protein (APP) is a type I transmembrane protein of unknown physiological function. Its soluble secreted form (sAPP) shows similarities with growth factors and increases the in vitro proliferation of embryonic neural stem cells. As neurogenesis is an ongoing process in the adult mammalian brain, we have investigated a role for sAPP in adult neurogenesis. We show that the subventricular zone (SVZ) of the lateral ventricle, the largest neurogenic area of the adult brain, is a major sAPP binding site and that binding occurs on progenitor cells expressing the EGF receptor. These EGF-responsive cells can be cultured as neurospheres (NS). In vitro, EGF provokes soluble APP (sAPP) secretion by NS and anti-APP antibodies antagonize the EGF-induced NS proliferation. In vivo, sAPP infusions increase the number of EGF-responsive progenitors through their increased proliferation. Conversely, blocking sAPP secretion or downregulating APP synthesis decreases the proliferation of EGF-responsive cells, which leads to a reduction of the pool of progenitors. These results reveal a new function for sAPP as a regulator of SVZ progenitor proliferation in the adult central nervous system.
淀粉样前体蛋白（APP）是一种生理功能未知的I型跨膜蛋白。其可溶性分泌形式（sAPP）与生长因子具有相似性，并能增加胚胎神经干细胞的体外增殖。由于神经发生是成年哺乳动物大脑中一个持续进行的过程，我们研究了sAPP在成年神经发生中的作用。我们发现，侧脑室的室下区（SVZ）是成年大脑中最大的神经发生区域，是主要的sAPP结合位点，且结合发生在表达表皮生长因子（EGF）受体的祖细胞上。这些对EGF有反应的细胞可以培养成神经球（NS）。在体外，EGF可促使NS分泌可溶性APP（sAPP），抗APP抗体可拮抗EGF诱导的NS增殖。在体内，注入sAPP可通过增加增殖来增加对EGF有反应的祖细胞数量。相反，阻断sAPP分泌或下调APP合成会降低对EGF有反应的细胞的增殖，从而导致祖细胞池减少。这些结果揭示了sAPP作为成年中枢神经系统中SVZ祖细胞增殖调节因子的新功能。
