Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic.
Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic.
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DOI：
10.3233/jad-131370
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Hook V
中科院分区：
文献类型：
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作者：
Hook G;Yu J;Toneff T;Kindy M;Hook V
焦谷氨酸淀粉样β肽（pGlu-Aβ）是阿尔茨海默病（AD）大脑中存在的特别有害的淀粉样β肽（Aβ）形式。 pGlu-Aβ 肽是全长 Aβ 肽 (flAβ(1-40/42)) 的 N 端截短形式，其中 N 端谷氨酸环化为焦谷氨酸，生成 pGlu-Aβ(3-40/42)。 β-分泌酶裂解淀粉样蛋白-β 前体蛋白 (AβPP) 会产生 flAβ(1-40/42)，但尚不清楚 β-分泌酶 BACE1 或替代的 β-分泌酶组织蛋白酶 B (CatB) 是否参与 pGlu-Aβ 的产生。因此，本研究研究了这些蛋白酶的基因敲除对转基因 AβPPLon 小鼠脑内 pGlu-Aβ 水平的影响，该小鼠表达 AβPP 亚型 695，并具有大多数 AD 患者中发现的野生型 (wt) β-分泌酶活性。 CatB 基因的敲除或过表达分别减少或增加了 pGlu-Aβ(3-40/42)、flAβ(1-40/42) 和 pGlu-Aβ 斑块负载，但 BACE1 基因敲除对转基因小鼠的这些参数没有影响。用E64d（一种 CatB 的半胱氨酸蛋白酶抑制剂）治疗 AβPPLon 小鼠，也可减少脑部 pGlu-Aβ(3-42)、flAβ(1-40/42) 和 pGlu-Aβ 斑块负荷。用 CatB 抑制剂 CA074Me 处理神经元样嗜铬细胞，导致活性依赖性、受调节的分泌途径释放的 pGlu-Aβ(3-40) 水平降低。此外，CatB 敲除和 E64d 治疗先前已被证明可以改善 AβPPLon 小鼠的记忆缺陷。这些数据说明了 CatB 在产生 pGlu-Aβ 和 flAβ 中的作用，而 pGlu-Aβ 和 flAβ 是 AD 发展的关键因素。讨论了 CatB 抑制剂，特别是 E64d 及其衍生物作为 BACE1 抑制剂替代品治疗 AD 患者的优势。
Pyroglutamate amyloid-β peptides (pGlu-Aβ) are particularly pernicious forms of amyloid-β peptides (Aβ) present in Alzheimer’s disease (AD) brains. pGlu-Aβ peptides are N-terminally truncated forms of full-length Aβ peptides (flAβ(1-40/42)) in which the N-terminal glutamate is cyclized to pyroglutamate to generate pGlu-Aβ(3-40/42). β-secretase cleavage of amyloid-β precursor protein (AβPP) produces flAβ(1-40/42), but it is not yet known whether the β-secretase BACE1 or the alternative β-secretase cathepsin B (CatB) participate in the production of pGlu-Aβ. Therefore, this study examined the effects of gene knockout of these proteases on brain pGlu-Aβ levels in transgenic AβPPLon mice, which express AβPP isoform 695 and have the wild-type (wt) β-secretase activity found in most AD patients. Knockout or overexpression of the CatB gene reduced or increased, respectively, pGlu-Aβ(3-40/42), flAβ(1-40/42), and pGlu-Aβ plaque load, but knockout of the BACE1 gene had no effect on those parameters in the transgenic mice. Treatment of AβPPLon mice with E64d, a cysteine protease inhibitor of CatB, also reduced brain pGlu-Aβ(3-42), flAβ(1-40/42), and pGlu-Aβ plaque load. Treatment of neuronal-like chromaffin cells with CA074Me, an inhibitor of CatB, resulted in reduced levels of pGlu-Aβ(3-40) released from the activity-dependent, regulated secretory pathway. Moreover, CatB knockout and E64d treatment has been previously shown to improve memory deficits in the AβPPLon mice. These data illustrate the role of CatB in producing pGlu-Aβ and flAβ that participate as key factors in the development of AD. The advantages of CatB inhibitors, especially E64d and its derivatives, as alternatives to BACE1 inhibitors in treating AD patients are discussed.