Soluble γ-secretase modulators selectively inhibit the production of the 42-amino acid amyloid ß peptide variant and augment the production of multiple carboxy-truncated amyloid ß species.
Biochemistry
; 53(4): 702-13, 2014 Feb 04.
Article
em En
| MEDLINE
| ID: mdl-24401146
ABSTRACT
Alzheimer's disease (AD) is characterized pathologically by an abundance of extracellular neuritic plaques composed primarily of the 42-amino acid amyloid ß peptide variant (Aß42). 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 Aß42 compared to the levels of Aß40. We previously reported the characterization of a series of aminothiazole-bridged aromates termed aryl aminothiazole γ-secretase modulators or AGSMs [Kounnas, M. Z., et al. (2010) Neuron 67, 769-780] and showed their potential for use in the treatment of FAD [Wagner, S. L., et al. (2012) Arch. Neurol. 69, 1255-1258]. 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 γ-secretase modulators (SGSMs) potently lowered Aß42 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 Aß42 levels. The effects of one potent SGSM on Aß peptide production were verified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, showing enhanced production of a number of carboxy-truncated Aß species. This SGSM also inhibited Aß42 peptide production in a highly purified reconstituted γ-secretase in vitro assay system and retained the ability to modulate γ-secretase-mediated proteolysis in a stably transfected cell culture model overexpressing a human PS1 mutation validating the potential for use in FAD.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos beta-Amiloides
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Secretases da Proteína Precursora do Amiloide
Limite:
Humans
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos