Soluble 纬-Secretase Modulators Selectively Inhibit the Production of the 42-Amino Acid Amyloid 尾 Peptide Variant and Augment the Production of Multiple Carboxy-Truncated Amyloid 尾 Species
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- 作者：Steven L. Wagner ; Can Zhang ; Soan Cheng ; Phuong Nguyen ; Xulun Zhang ; Kevin D. Rynearson ; Rong Wang ; Yueming Li ; Sangram S. Sisodia ; William C. Mobley ; Rudolph E. Tanzi
- 刊名：Biochemistry
- 出版年：2014
- 出版时间：February 4, 2014
- 年：2014
- 卷：53
- 期：4
- 页码：702-713
- 全文大小：610K
- ISSN：1520-4995
文摘
Alzheimer鈥檚 disease (AD) is characterized pathologically by an abundance of extracellular neuritic plaques composed primarily of the 42-amino acid amyloid 尾 peptide variant (A尾42). In the majority of familial AD (FAD) cases, e.g., those harboring mutations in presenilin 1 (PS1), there is a relative increase in the levels of A尾42 compared to the levels of A尾40. We previously reported the characterization of a series of aminothiazole-bridged aromates termed aryl aminothiazole 纬-secretase modulators or AGSMs [Kounnas, M. Z., et al. (2010) Neuron 67, 769鈥?80] and showed their potential for use in the treatment of FAD [Wagner, S. L., et al. (2012) Arch. Neurol. 69, 1255鈥?258]. Here we describe a series of GSMs with physicochemical properties improved compared to those of AGSMs. Specific heterocycle replacements of the phenyl rings in AGSMs provided potent molecules with improved aqueous solubilities. A number of these soluble 纬-secretase modulators (SGSMs) potently lowered A尾42 levels without inhibiting proteolysis of Notch or causing accumulation of amyloid precursor protein carboxy-terminal fragments, even at concentrations approximately 1000-fold greater than their IC50 values for reducing A尾42 levels. The effects of one potent SGSM on A尾 peptide production were verified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, showing enhanced production of a number of carboxy-truncated A尾 species. This SGSM also inhibited A尾42 peptide production in a highly purified reconstituted 纬-secretase in vitro assay system and retained the ability to modulate 纬-secretase-mediated proteolysis in a stably transfected cell culture model overexpressing a human PS1 mutation validating the potential for use in FAD.