Novel N-terminal cleavage of APP precludes Abeta generation in ACAT-defective AC29 cells.
Novel N-terminal cleavage of APP precludes Abeta generation in ACAT-defective AC29 cells.
复制标题
DOI：
10.1007/s12031-008-9088-0
复制
发表时间：
2009-01
影响因子：
3.1
通讯作者：
Kovacs, Dora M.
中科院分区：
文献类型：
--
作者：
Huttunen, Henri J.;Puglielli, Luigi;Ellis, Blake C.;Ingano, Laura A. MacKenzie;Kovacs, Dora M.
在所有形式的阿尔茨海默病中发生的常见致病事件是淀粉样β-肽（Aβ）在负责高级认知功能的脑区域中的进行性积累。酰基辅酶A的抑制：胆固醇酰基转移酶（ACAT）从游离胆固醇和脂肪酸产生细胞内胆固醇酯，减少淀粉样前体蛋白（APP）的Aβ生物合成。在此，我们使用ACAT活性缺陷的AC 29细胞，以显示ACAT活性引导APP朝向或远离一种新的蛋白水解途径，该途径取代APP的α和淀粉样β裂解。这种替代途径涉及APP全蛋白在Glu 281处的新裂解，这与AC 29细胞中ACAT活性降低和Aβ生成相关。这种甾醇依赖性的APP裂解发生在细胞表面APP内化后的内体区室中。所产生的新的C端片段APP-C470注定要被蛋白酶体降解，限制了APP对Aβ生成系统的可用性。针对新的裂解途径的APP分子的比例由细胞中游离胆固醇和胆固醇酯的比例调节。这些结果表明，亚细胞胆固醇分布可能是一个重要的调节APP全蛋白的细胞命运，可能存在几个竞争性的蛋白水解系统负责APP内体区室内的加工。
A common pathogenic event that occurs in all forms of Alzheimer’s disease is the progressive accumulation of amyloid β-peptide (Aβ) in brain regions responsible for higher cognitive functions. Inhibition of acyl-coenzyme A: cholesterol acyltransferase (ACAT), which generates intracellular cholesteryl esters from free cholesterol and fatty acids, reduces the biogenesis of the Aβ from the amyloid precursor protein (APP). Here we have used AC29 cells, defective in ACAT activity, to show that ACAT activity steers APP either toward or away from a novel proteolytic pathway that replaces both α and the amyloidogenic β cleavages of APP. This alternative pathway involves a novel cleavage of APP holoprotein at Glu281, which correlates with reduced ACAT activity and Aβ generation in AC29 cells. This sterol-dependent cleavage of APP occurs in the endosomal compartment after internalization of cell surface APP. The resulting novel C-terminal fragment APP-C470 is destined to proteasomal degradation limiting the availability of APP for the Aβ generating system. The proportion of APP molecules that are directed to the novel cleavage pathway is regulated by the ratio of free cholesterol and cholesteryl esters in cells. These results suggest that subcellular cholesterol distribution may be an important regulator of the cellular fate of APP holoprotein and that there may exist several competing proteolytic systems responsible for APP processing within the endosomal compartment.
登录
查看更多内容
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
168.9
作者：
Jick, H;Zornberg, GL;Drachman, DA
通讯作者：
Drachman, DA
影响因子：
1.7
作者：
Frears, ER;Stephens, DJ;Austen, BM
通讯作者：
Austen, BM
影响因子：
4.7
作者：
Parkin, ET;Hussain, I;Hooper, NM
通讯作者：
Hooper, NM
影响因子：
3.5
作者：
Huttunen, Henri J.;Greco, Christopher;Kovacs, Dora M.
通讯作者：
Kovacs, Dora M.