کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2040369 | 1073108 | 2016 | 15 صفحه PDF | دانلود رایگان |
• The AD-linked protease BACE1 cleaves APP to produce toxic β-amyloid peptides
• BACE1 also cleaves the non-amyloid substrates NRG1 and L1
• BACE1 cleavage of NRG1 and L1 is endocytosis-independent, unlike the cleavage of APP
• The endosomally targeted BACE1 inhibitor spares NRG1 and L1 but inhibits APP processing
SummaryDevelopment of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic β-amyloid (Aβ) peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit β-cleavage of non-amyloid substrates like Neuregulin. We report that β-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of β-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by β-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal β-secretase by an endosomally targeted β-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. β-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects.
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Journal: - Volume 14, Issue 9, 8 March 2016, Pages 2127–2141