Dementia Research Group, Institute of Clinical Neurosciences, Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, UK.
J Neuropathol Exp Neurol. 2011 Nov;70(11):944-59. doi: 10.1097/NEN.0b013e3182345e46.
There is increasing evidence that deficient clearance of β-amyloid (Aβ) contributes to its accumulation in late-onset Alzheimer disease (AD). Several Aβ-degrading enzymes, including neprilysin (NEP), insulin-degrading enzyme, and endothelin-converting enzyme reduce Aβ levels and protect against cognitive impairment in mouse models of AD. The activity of several Aβ-degrading enzymes rises with age and increases still further in AD, perhaps as a physiological response to minimize the buildup of Aβ. The age- and disease-related changes in expression of more recently recognized Aβ-degrading enzymes (e.g. NEP-2 and cathepsin B) remain to be investigated, and there is strong evidence that reduced NEP activity contributes to the development of cerebral amyloid angiopathy. Regardless of the role of Aβ-degrading enzymes in the development of AD, experimental data indicate that increasing the activity of these enzymes (NEP in particular) has therapeutic potential in AD, although targeting their delivery to the brain remains a major challenge. The most promising current approaches include the peripheral administration of agents that enhance the activity of Aβ-degrading enzymes and the direct intracerebral delivery of NEP by convection-enhanced delivery. In the longer term, genetic approaches to increasing the intracerebral expression of NEP or other Aβ-degrading enzymes may offer advantages.
越来越多的证据表明β-淀粉样蛋白（Aβ）清除不足导致其在迟发性阿尔茨海默病（AD）中积累。几种 Aβ 降解酶，包括 Neprilysin（NEP）、胰岛素降解酶和内皮素转换酶，可降低 Aβ 水平并预防 AD 小鼠模型的认知障碍。几种 Aβ 降解酶的活性随年龄增长而升高，在 AD 中进一步升高，这可能是一种减轻 Aβ 积累的生理反应。最近发现的 Aβ 降解酶（如 Neprilysin-2 和组织蛋白酶 B）的表达随年龄和疾病的变化仍有待研究，并且有强有力的证据表明 NEP 活性降低导致脑淀粉样血管病的发生。无论 Aβ 降解酶在 AD 发展中的作用如何，实验数据表明，增加这些酶（尤其是 NEP）的活性在 AD 中具有治疗潜力，尽管将其递送到大脑仍然是一个主要挑战。目前最有前途的方法包括外周给予增强 Aβ 降解酶活性的药物，以及通过对流增强递送直接向大脑内递送 NEP。从长远来看，增加脑内 NEP 或其他 Aβ 降解酶的表达的遗传方法可能具有优势。
