Substrate-targeting γ-secretase modulators

Thomas L. Kukar, Thomas B. Ladd, Maralyssa A. Bann, Patrick C. Fraering, Rajeshwar Narlawar, Ghulam M. Maharvi, Brent Healy, Robert Chapman, Alfred T. Welzel, Robert W. Price, Brenda Moore, Vijayaraghavan Rangachari, Bernadette Cusack, Jason Eriksen, Karen Jansen-West, Christophe Verbeeck, Debra Yager, Christopher Eckman, Wenjuan Ye, Sarah SagiBarbara A. Cottrell, Justin Torpey, Terrone L. Rosenberry, Abdul Fauq, Michael S. Wolfe, Boris Schmidt, Dominic M. Walsh, Edward H. Koo, Todd E. Golde

Research output: Contribution to journalArticle

259 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)925-929
Number of pages5
JournalNature
Volume453
Issue number7197
DOIs
StatePublished - Jun 12 2008

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Substrate-targeting γ-secretase modulators'. Together they form a unique fingerprint.

  • Cite this

    Kukar, T. L., Ladd, T. B., Bann, M. A., Fraering, P. C., Narlawar, R., Maharvi, G. M., Healy, B., Chapman, R., Welzel, A. T., Price, R. W., Moore, B., Rangachari, V., Cusack, B., Eriksen, J., Jansen-West, K., Verbeeck, C., Yager, D., Eckman, C., Ye, W., ... Golde, T. E. (2008). Substrate-targeting γ-secretase modulators. Nature, 453(7197), 925-929. https://doi.org/10.1038/nature07055