Editors' ChoiceAlzheimer’s Disease

Tactical Target

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Science Signaling  05 May 2009:
Vol. 2, Issue 69, pp. ec158
DOI: 10.1126/scisignal.269ec158

Intramembrane proteolysis by the γ-secretase complex is importantduring development and in the pathology of Alzheimer’s disease.γ-Secretase has usually been considered as a homogeneous activity.Serneels et al. (see thePerspective by Golde and Kukar) now show that the Aph1B componentof the γ-secretase complex is responsible for the generationof long β-amyloid species involved in Alzheimer's disease.In a mouse model of Alzheimer’s disease, full knockout of Aph1Bimproved disease phenotypes, without the sort of toxicity previouslyobserved when targeting γ-secretase more generally.

L. Serneels, J. Van Biervliet, K. Craessaerts, T. Dejaegere, K. Horré, T. Van Houtvin, H. Esselmann, S. Paul, M. K. Schäfer, O. Berezovska, B. T. Hyman, B. Sprangers, R. Sciot, L. Moons, M. Jucker, Z. Yang, P. C. May, E. Karran, J. Wiltfang, R. D’Hooge, B. De Strooper, γ-Secretase heterogeneity in the Aph1 subunit: Relevance for Alzheimer’s disease. Science 324, 639–642 (2009). [Abstract] [Full Text]

T. E. Golde, T. L. Kukar, Avoiding unintended toxicity. Science 324, 603–604 (2009). [Summary] [Full Text]