Departments of Pharmacology and Experimental Therapeutics, Boston University Medical Campus, Boston, MA 02118, USA.
J Alzheimers Dis. 2012;29(2):329-40. doi: 10.3233/JAD-2011-111472.
Sporadic Alzheimer's disease (AD) patients have low amyloid-β peptide (Aβ) clearance in the central nervous system. The peripheral Aβ clearance may also be important but its role in AD remains unclear. We aimed to study the Aβ degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. Using the fluorogenic substrate V (a substrate of IDE and other metalloproteases), we showed that human serum degraded the substrate V, and the activity was inhibited by adding increasing dose of Aβ. The existence of IDE activity was demonstrated by the inhibition of insulin, amylin, or EDTA, and further confirmed by immunocapture of IDE using monoclonal antibodies. The involvement of ACE was indicated by the ability of the ACE inhibitor, lisinopril, to inhibit the substrate V degradation. To test the variations of substrate V degradation in humans, we used serum samples from a homebound elderly population with cognitive diagnoses. Compared with the elderly who had normal cognition, those with probable AD and amnestic mild cognitive impairment (amnestic MCI) had lower peptidase activities. Probable AD or amnestic MCI as an outcome remained negatively associated with serum substrate V degradation activity after adjusting for the confounders. The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Aβ degradation may be important for the AD pathogenesis. More studies are needed to specify each Aβ degrading protease in blood as a useful biomarker and a possible treatment target for AD.
散发性阿尔茨海默病（AD）患者的中枢神经系统中β淀粉样肽（Aβ）清除率较低。外周 Aβ 清除率也可能很重要，但它在 AD 中的作用尚不清楚。我们旨在研究血液中的 Aβ 降解蛋白酶，包括胰岛素降解酶（IDE）、血管紧张素转换酶（ACE）等。我们使用荧光底物 V（IDE 和其他金属蛋白酶的底物），表明人血清降解了底物 V，并且随着 Aβ 剂量的增加，其活性受到抑制。通过添加胰岛素、淀粉样肽或 EDTA 抑制 IDE 活性，证明了 IDE 活性的存在，并用单克隆抗体免疫捕获进一步证实了 IDE 的存在。ACE 抑制剂赖诺普利能够抑制底物 V 降解，表明 ACE 参与其中。为了测试人类体内底物 V 降解的变化，我们使用了来自认知诊断的居家老年人的血清样本。与认知正常的老年人相比，可能患有 AD 和遗忘型轻度认知障碍（amnestic MCI）的老年人的肽酶活性较低。在调整混杂因素后，可能患有 AD 或遗忘型 MCI 的结果与血清底物 V 降解活性呈负相关。与血管性痴呆患者相比，可能患有 AD 的老年人血清底物 V 降解活性较低。介导 Aβ 降解的血液蛋白酶可能对 AD 的发病机制很重要。需要更多的研究来确定血液中的每种 Aβ 降解蛋白酶作为 AD 的有用生物标志物和潜在治疗靶点。
