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Interactions between the amyloid precursor protein C-terminal domain and G proteins mediate calcium dysregulation and amyloid β toxicity in Alzheimer’s disease
Article first published online: 2 APR 2009
DOI: 10.1111/j.1742-4658.2009.06997.x
© 2009 University of California, San Diego. Journal compilation © 2009 FEBS
Additional Information
How to Cite
Shaked, G. M., Chauv, S., Ubhi, K., Hansen, L. A. and Masliah, E. (2009), Interactions between the amyloid precursor protein C-terminal domain and G proteins mediate calcium dysregulation and amyloid β toxicity in Alzheimer’s disease. FEBS Journal, 276: 2736–2751. doi: 10.1111/j.1742-4658.2009.06997.x
Publication History
- Issue published online: 27 APR 2009
- Article first published online: 2 APR 2009
- (Received 11 December 2008, revised 22 February 2009, accepted 9 March 2009)
Keywords:
- caspase;
- endoplasmic reticulum;
- neurodegeneration;
- voltage gated calcium channels
Alzheimer’s disease is characterized by neuropathological accumulations of amyloid β(1–42) [Aβ(1–42)], a cleavage product of the amyloid precursor protein (APP). Recent studies have highlighted the role of APP in Aβ-mediated toxicity and have implicated the G-protein system; however, the exact mechanisms underlying this pathway are as yet undetermined. In this context, we sought to investigate the role of calcium upregulation following APP-dependent, Aβ-mediated G-protein activation. Initial studies on the interaction between APP, Aβ and Go proteins demonstrated that the interaction between APP, specifically its C-terminal -YENPTY- region, and Go was reduced in the presence of Aβ. Cell death and calcium influx in Aβ-treated cells were shown to be APP dependent and to involve G-protein activation because these effects were blocked by use of the G-protein inhibitor, pertussis toxin. Collectively, these results highlight a role for the G-protein system in APP-dependent, Aβ-induced toxicity and calcium dysregulation. Analysis of the APP:Go interaction in human brain samples from Alzheimer’s disease patients at different stages of the disease revealed a decrease in the interaction, correlating with disease progression. Moreover, the reduced interaction between APP and Go was shown to correlate with an increase in membrane Aβ levels and G-protein activity, showing for first time that the APP:Go interaction is present in humans and is responsive to Aβ load. The results presented support a role for APP in Aβ-induced G-protein activation and suggest a mechanism by which basal APP binding to Go is reduced under pathological loads of Aβ, liberating Go and activating the G-protein system, which may in turn result in downstream effects including calcium dysregulation. These results also suggest that specific antagonists of G-protein activity may have a therapeutic relevance in Alzheimer’s disease.