Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibition

The protease BACE1 is a major drug target for Alzheimer’s disease, but chronic BACE1 inhibition is associated with non-progressive worsening that may be caused by modulation of unknown physiological BACE1 substrates. To identify in vivo-relevant BACE1 substrates we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as a new in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. In conclusion, BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans.

BACE1蛋白酶是阿尔茨海默病的首要药物靶点，然而，慢性BACE1抑制与可能由未知生理BACE1底物的调节引起的非进展性恶化相关。为识别体内相关的BACE1底物，我们对非人灵长类动物的脑脊液（CSF）进行了药理学蛋白质组学分析，该分析是在急性使用BACE抑制剂治疗后进行的。除了SEZ6之外，观察到最强的、剂量依赖性的降低出现在促炎性细胞因子受体gp130/IL6ST上，我们将它确立为新的体内BACE1底物。在BACE抑制剂的临床试验中，来自人类CSF的gp130也出现了降低，在BACE1缺陷小鼠的血浆中也是如此。从机制上讲，我们证明了BACE1直接切割gp130，从而减轻了膜结合的gp130，增加了可溶性gp130的丰度，并控制了神经元IL-6信号传导和神经元在生长因子剥夺后的存活中gp130的功能。总之，BACE1是gp130功能的新调节因子。BACE1切割的可溶性gp130可能作为药代动力学BACE1活性标志物，以减少人类慢性BACE1抑制的副作用。