Xia W
Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 616, Boston, MA 02115, USA.
Curr Neurol Neurosci Rep. 2001 Sep;1(5):422-7. doi: 10.1007/s11910-001-0101-z.
Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid fibrils composed of the amyloid beta-protein (A beta) in senile plaques. A beta is derived from the beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavages. beta-secretase was recently identified to be a membrane-anchored aspartyl protease that is widely distributed in subcellular compartments, including Golgi, trans-Golgi network, and endosomes. Although definitive identification of gamma-secretase will require reconstituting its activity in vitro, mounting evidence suggests that gamma-secretase is an unusual intramembrane-cleaving aspartyl protease. Two intramembranous aspartate residues in presenilin (PS) are absolutely required for A beta generation. Three classes of gamma-secretase inhibitors can directly bind to PS, strongly supporting the hypothesis of PSI as gamma-secretase. These results provide the molecular basis for therapeutic interventions that reduce A beta accumulation in AD patients by inhibiting beta- or gamma-secretase.
阿尔茨海默病（AD）的特征是由淀粉样β蛋白（Aβ）组成的淀粉样纤维在老年斑中进行性积累。Aβ是β淀粉样前体蛋白（APP）经β和γ分泌酶切割后产生的。β分泌酶最近被确定为一种膜锚定天冬氨酸蛋白酶，广泛分布于包括高尔基体、反式高尔基体网络和内体在内的亚细胞区室中。尽管γ分泌酶的确切鉴定需要在体外重建其活性，但越来越多的证据表明γ分泌酶是一种不同寻常的膜内切割天冬氨酸蛋白酶。早老素（PS）中的两个膜内天冬氨酸残基是生成Aβ绝对必需的。三类γ分泌酶抑制剂可直接与PS结合，有力支持了PS作为γ分泌酶的假说。这些结果为通过抑制β或γ分泌酶来减少AD患者Aβ积累的治疗干预提供了分子基础。
