Tschirner Sarah K, Zuchero Y Joy Yu, Getz Jennifer A, Müller Stephan A, Nalbach Karsten, Kennedy Matthew E, Lewcock Joseph W, Lichtenthaler Stefan F
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Neuroproteomics, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany.
Denali Therapeutics Inc., South San Francisco, California, USA.
Mol Cell Proteomics. 2025 Jun 4;24(7):101012. doi: 10.1016/j.mcpro.2025.101012.
The β-secretase β-site APP cleaving enzyme 1 (BACE1) is a major drug target for Alzheimer's disease (AD). Clinically tested BACE1 inhibitors induced unexpected cognitive side effects that may stem from their cross-inhibition of the homologous protease BACE2. Yet, little is known about BACE2 functions and substrates in vivo, and no biomarker is available to monitor the extent of BACE2 inhibition in vivo, particularly in cerebrospinal fluid (CSF). To identify a potential CSF biomarker for monitoring BACE2 activity, we analyzed the CSF proteome changes in non-human primates after treatment with a BACE1-selective inhibitor (a brain-targeted monoclonal antibody) in comparison to verubecestat, a clinically tested small-molecule drug inhibiting both BACE1 and BACE2. Acute treatment with either the antibody or verubecestat similarly reduced CSF abundance of the cleavage products of several known BACE1 substrates, including SEZ6, gp130, and CACHD1, demonstrating similar target engagement in vivo. One CSF protein, vascular cell adhesion protein 1 (VCAM-1), was only reduced upon inhibition with verubecestat, but not upon BACE1-selective inhibition with the antibody. We conclude that VCAM-1 is a promising biomarker candidate for monitoring BACE2 inhibition in CSF, which is instrumental for the development of BACE1-selective inhibitors for the prevention of AD.
β-分泌酶β位点APP裂解酶1（BACE1）是阿尔茨海默病（AD）的主要药物靶点。临床测试的BACE1抑制剂引发了意想不到的认知副作用，这可能源于它们对同源蛋白酶BACE2的交叉抑制。然而，关于BACE2在体内的功能和底物知之甚少，并且没有生物标志物可用于监测体内BACE2的抑制程度，尤其是在脑脊液（CSF）中。为了确定一种潜在的用于监测BACE2活性的脑脊液生物标志物，我们分析了与临床测试的同时抑制BACE1和BACE2的小分子药物维鲁比卡司他相比，用BACE1选择性抑制剂（一种脑靶向单克隆抗体）治疗后非人灵长类动物脑脊液蛋白质组的变化。用抗体或维鲁比卡司他进行急性治疗同样降低了几种已知BACE1底物（包括SEZ6、gp130和CACHD1）裂解产物的脑脊液丰度，表明在体内有相似的靶点结合。一种脑脊液蛋白，血管细胞粘附蛋白1（VCAM-1），仅在用维鲁比卡司他抑制时减少，而在用抗体进行BACE1选择性抑制时未减少。我们得出结论，VCAM-1是监测脑脊液中BACE2抑制的一个有前景的生物标志物候选物，这对开发用于预防AD的BACE1选择性抑制剂至关重要。
