γ-Secretase Cleavage and Binding to FE65 Regulate the Nuclear Translocation of 
the Intracellular C-Terminal Domain (ICD) of the APP Family of Proteins

Walsh, Dominic M.; Fadeeva, Julia V.; LaVoie, Matthew J.; Paliga, Krzysztof; Eggert, Simone; Kimberly, W. Taylor; Wasco, Wilma; Selkoe, Dennis J.

doi:10.1021/bi027375c

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γ-Secretase Cleavage and Binding to FE65 Regulate the Nuclear Translocation of the Intracellular C-Terminal Domain (ICD) of the APP Family of Proteins

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https://doi.org/10.1021/bi027375c
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Citation

Walsh, D. M., Fadeeva, J. V., LaVoie, M. J., Paliga, K., Eggert, S., Kimberly, W. T., et al. (2003). γ-Secretase Cleavage and Binding to FE65 Regulate the Nuclear Translocation of the Intracellular C-Terminal Domain (ICD) of the APP Family of Proteins. Biochemistry, 42(22), 6664-6673. doi:10.1021/bi027375c.

Cite as: https://hdl.handle.net/21.11116/0000-000E-3E2C-D

Abstract

Regulated intramembrane proteolysis (RIP) of the amyloid precursor protein (APP) produces amyloid β-protein (Aβ), the probable causative agent of Alzheimer's disease (AD), and is therefore an important target for therapeutic intervention. However, there is a burgeoning consensus that γ-secretase, one of the proteases that generates Aβ, is also critical for the signal transduction of APP and a growing list of other receptors. APP is a member of a gene family that includes two amyloid precursor-like proteins, APLP1 and APLP2. Although APP and the APLPs undergo similar proteolytic processing, there is little information about the role of their γ-secretase-generated intracellular domains (ICDs). Here, we show that APLP1 and 2 undergo presenilin-dependent RIP similar to APP, resulting in the release of a ∼6 kDa ICD for each protein. Each of the ICDs are degraded by an insulin degrading enzyme-like activity, but they can be stabilized by members of the FE65 family and translocate to the nucleus. Given that modulation of APP processing is a therapeutic target and that the APLPs are processed in a manner similar to APP, any strategy aimed at altering APP proteolysis will have to take into account possible effects on signaling by APLP 1 and 2.