Sisodia S S, Price D L
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
FASEB J. 1995 Mar;9(5):366-70. doi: 10.1096/fasebj.9.5.7896005.
A major histopathological hallmark of Alzheimer's disease (AD) is the presence of amyloid deposits in the parenchyma of the amygdala, hippocampus, and neocortex. The principal component of amyloid is the beta-amyloid protein (A beta), a 39-43 amino acid peptide composed of a portion of the transmembrane domain and the extracellular domain of the amyloid precursor protein (APP). APP occurs as several A beta-containing isoforms of 695, 751, and 770 amino acids, with the latter two APP containing a domain that shares structural and functional homologies with Kunitz serine protease inhibitors. In cultured cells, APP mature through the constitutive secretory pathway, and some cell surface-bound APP are cleaved by an enzyme, designated as alpha-secretase, within the A beta domain, an event that precludes A beta amyloidogenesis. Several studies have delineated two additional pathways of APP processing: first, an endosomal/lysosomal pathway generates a complex set of APP-related membrane-bound fragments, some of which contain the entire A beta sequence; and, second, by mechanisms which are not fully understood, A beta 1-40 is secreted into the conditioned medium in vitro and is present in cerebrospinal fluid in vivo. The intracellular sites of enzymes responsible for proteolytic cleavage at the NH2 and COOH termini of A beta, termed gamma- and beta-secretase, respectively, have not been identified. Finally, recent molecular genetic investigations have identified a variety of mutations in APP that segregate with early-onset familial AD and with hereditary cerebral hemorrhage with amyloid, Dutch type (HCHWA-D). Several of these mutations appear to influence APP processing and result in the production of higher levels or longer A beta-related peptides that are inherently more fibrillogenic. Although a variety of lines of evidence implicates APP/A beta in AD, the mechanisms by which A beta influences the biology and vulnerability of neural cells are not fully understood but are very active areas of investigation. This review focuses on the present state of our understanding of APP and A beta in the context of AD.
阿尔茨海默病（AD）的一个主要组织病理学特征是在杏仁核、海马体和新皮质的实质中存在淀粉样沉积物。淀粉样蛋白的主要成分是β-淀粉样蛋白（Aβ），这是一种由39 - 43个氨基酸组成的肽，由淀粉样前体蛋白（APP）的跨膜结构域和细胞外结构域的一部分组成。APP以695、751和770个氨基酸的几种含Aβ的异构体形式存在，后两种APP含有一个与Kunitz丝氨酸蛋白酶抑制剂具有结构和功能同源性的结构域。在培养细胞中，APP通过组成型分泌途径成熟，一些细胞表面结合的APP在Aβ结构域内被一种称为α-分泌酶的酶切割，这一事件可防止Aβ淀粉样蛋白生成。多项研究已经阐明了APP加工的另外两条途径：第一，内体/溶酶体途径产生一组复杂的与APP相关的膜结合片段，其中一些包含完整的Aβ序列；第二，通过尚未完全了解的机制，Aβ1 - 40在体外被分泌到条件培养基中，并在体内存在于脑脊液中。分别负责在Aβ的NH2和COOH末端进行蛋白水解切割的酶的细胞内位点，即γ-分泌酶和β-分泌酶，尚未被确定。最后，最近的分子遗传学研究已经在APP中鉴定出多种突变，这些突变与早发性家族性AD以及荷兰型遗传性脑出血伴淀粉样变（HCHWA - D）相关。其中一些突变似乎影响APP加工，并导致产生更高水平或更长的Aβ相关肽，这些肽本质上更易形成纤维。尽管各种证据表明APP/Aβ与AD有关，但Aβ影响神经细胞生物学特性和易损性的机制尚未完全了解，不过是非常活跃的研究领域。本综述重点关注在AD背景下我们对APP和Aβ目前的理解状态。
