Brain Shuttle Neprilysin reduces central Amyloid-β levels
Brain Shuttle Neprilysin reduces central Amyloid-β levels
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DOI：
10.1371/journal.pone.0229850
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发表时间：
2020-03-10
期刊：
影响因子：
3.7
通讯作者：
Urich, Eduard
中科院分区：
文献类型：
--
作者：
Campos, Christopher R.;Kemble, Alicia M.;Urich, Eduard
减少大脑中的β淀粉样蛋白（A β）对于推进阿尔茨海默病的治疗具有重要意义。内源性金属肽酶neprilysin （NEP）已被确定为关键的A - β降解酶之一。利用脑穿梭（BS）运输系统将NEP输送到大脑为清除中央a β提供了一种很有前途的方法。我们将NEP的胞外催化结构域与活性或非活性BS模块融合。采用两种BS-NEP结构来研究剂量-反应和多次给药时血液和脑脊液（CSF）中的药代动力学/药效学关系。如前所述，NEP对血液中的A β降解非常有效，但在全身给药后对脑脊液室中的A β降解无效。相比之下，具有活性BS模块的NEP导致BS-NEP在脑脊液中暴露，随后脑脊液和脑实质中的a β大量减少。我们的数据表明，针对转铁蛋白受体的BS模块促进了a β降解酶穿过血脑屏障的运输，从而有效地降低了脑脊液和大脑中的a β水平。
Reducing Amyloid beta (A beta) in the brain is of fundamental importance for advancing the therapeutics for Alzheimer's disease. The endogenous metallopeptidase neprilysin (NEP) has been identified as one of the key A beta-degrading enzymes. Delivery of NEP to the brain by utilizing the Brain Shuttle (BS) transport system offers a promising approach for clearing central A beta. We fused the extracellular catalytic domain of NEP to an active or inactive BS module. The two BS-NEP constructs were used to investigate the pharmacokinetic/pharmacodynamics relationships in the blood and the cerebrospinal fluid (CSF) in dose-response and multiple dosing. As previously shown, NEP was highly effective at degrading A beta in blood but not in the CSF compartment after systemic administration. In contrast, the NEP with an active BS module led to a significant CSF exposure of BS-NEP, followed by substantial A beta reduction in CSF and brain parenchyma. Our data show that a BS module against the transferrin receptor facilitates the transport of an A beta degrading enzyme across the blood-brain barriers to efficiently reduce A beta levels in both CSF and brain.