1. Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
2. Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1025 Lausanne, Switzerland
3. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
4. Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universitaet Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany
5. Laboratory for Neurodegenerative Research, Conway Institute University College Dublin, Dublin 4, Republic of Ireland
6. Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA

Correspondence to: Thomas L. Kukar¹Todd E. Golde¹ Correspondence and requests for materials should be addressed to T.L.K. (Email: kukar.thomas@mayo.edu) and T.E.G. (Email: golde.todd@mayo.edu).

Abstract

Selective lowering of A42 levels (the 42-residue isoform of the amyloid- peptide) with small-molecule -secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease¹. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the -secretase complex, but instead labelled the -amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid- peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP -secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28–36 of amyloid-, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid- act as GSMs, and some GSMs alter the production of cell-derived amyloid- oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in A42 production and inhibition of amyloid- aggregation, which may synergistically reduce amyloid- deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets².

1. Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
2. Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1025 Lausanne, Switzerland
3. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
4. Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universitaet Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany
5. Laboratory for Neurodegenerative Research, Conway Institute University College Dublin, Dublin 4, Republic of Ireland
6. Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA

Correspondence to: Thomas L. Kukar¹Todd E. Golde¹ Correspondence and requests for materials should be addressed to T.L.K. (Email: kukar.thomas@mayo.edu) and T.E.G. (Email: golde.todd@mayo.edu).

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