TY - JOUR
T1 - Substrate-targeting γ-secretase modulators
AU - Kukar, Thomas L.
AU - Ladd, Thomas B.
AU - Bann, Maralyssa A.
AU - Fraering, Patrick C.
AU - Narlawar, Rajeshwar
AU - Maharvi, Ghulam M.
AU - Healy, Brent
AU - Chapman, Robert
AU - Welzel, Alfred T.
AU - Price, Robert W.
AU - Moore, Brenda
AU - Rangachari, Vijayaraghavan
AU - Cusack, Bernadette
AU - Eriksen, Jason
AU - Jansen-West, Karen
AU - Verbeeck, Christophe
AU - Yager, Debra
AU - Eckman, Christopher
AU - Ye, Wenjuan
AU - Sagi, Sarah
AU - Cottrell, Barbara A.
AU - Torpey, Justin
AU - Rosenberry, Terrone L.
AU - Fauq, Abdul
AU - Wolfe, Michael S.
AU - Schmidt, Boris
AU - Walsh, Dominic M.
AU - Koo, Edward H.
AU - Golde, Todd E.
N1 - Funding Information:
Acknowledgements This work was supported by grants from the US National Institutes of Health National Institute on Aging (to D.M.W., M.S.W., T.E.G., A.F. and E.H.K.), the AFAR CART award (T.E.G.), and the Mayo Foundation. T.L.K. was supported by the American Health Assistance Foundation ADR program, the Mayo ADRC, and a Robert and Clarice Smith Fellowship. A.T.W. was funded by a European Union 6th Framework Marie Curie Early Stage Training fellowship. P.C.F was supported by the Swiss National Science Foundation and by the NCCR ‘Neural Plasticity and Repair’. 21F12 was a gift from P. Seubert and D. Schenk.
PY - 2008/6/12
Y1 - 2008/6/12
N2 - Selective lowering of Aβ42 levels (the 42-residue isoform of the amyloid-β peptide) with small-molecule γ-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the γ-secretase complex, but instead labelled the β-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-β peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP γ-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-β, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-β act as GSMs, and some GSMs alter the production of cell-derived amyloid-β 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 Aβ42 production and inhibition of amyloid-β aggregation, which may synergistically reduce amyloid-β 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' targets.
AB - Selective lowering of Aβ42 levels (the 42-residue isoform of the amyloid-β peptide) with small-molecule γ-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the γ-secretase complex, but instead labelled the β-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-β peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP γ-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-β, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-β act as GSMs, and some GSMs alter the production of cell-derived amyloid-β 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 Aβ42 production and inhibition of amyloid-β aggregation, which may synergistically reduce amyloid-β 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' targets.
UR - http://www.scopus.com/inward/record.url?scp=45149105232&partnerID=8YFLogxK
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U2 - 10.1038/nature07055
DO - 10.1038/nature07055
M3 - Article
C2 - 18548070
AN - SCOPUS:45149105232
SN - 0028-0836
VL - 453
SP - 925
EP - 929
JO - Nature
JF - Nature
IS - 7197
ER -