Supramolecular assemblies formed by peptides or proteins termed amyloids are closely associated with numerous pathological conditions such as Alzheimer�s disease. This neurodegenerative disease is characterised by the abundance of amyloidogenic A�42 peptides generated by the proteolytic cleavage of the Amyloid Precursor Protein (APP) by the ?-secretase protease. Interestingly, compounds named ?-secretase modulators (GSMs) have been indentified with the ability to shift the protease cleavage specificity toward non-amyloidogenic fragments, thus opening opportunities for drug development. Whereas both the APP substrate and subunits of the ?-secretase complex have been previously proposed as the molecular target of GSMs, we confirmed the binding to the N-terminal fragment of presenilin using a potent acidic GSM modified with a photoreactive diazirine moiety. Altogether, this finding contributes to the elucidation of the puzzling mode of action of GSMs and provides insights into the sequence specificity of proteases.

Presenilin identified as the cellular target of acidic γ-secretase modulators using photoaffinity labeling

243rd National Meeting (2012)

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