Interactions between the amyloid precursor protein C-terminal domain and G proteins mediate calcium dysregulation and amyloid beta toxicity in Alzheimer's disease.
Alzheimer's disease is characterized by neuropathological accumulations of amyloid beta(1-42) [A beta(1-42)], a cleavage product of the amyloid precursor protein (APP). Recent studies have highlighted the role of APP in A beta-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, A beta-mediated G-protein activation. Initial studies on the interaction between APP, A beta and Go proteins demonstrated that the interaction between APP, specifically its C-terminal -YENPTY- region, and Go was reduced in the presence of A beta. Cell death and calcium influx in A beta-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, A beta-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 A beta levels and G-protein activity, showing for first time that the APP:Go interaction is present in humans and is responsive to A beta load. The results presented support a role for APP in A beta-induced G-protein activation and suggest a mechanism by which basal APP binding to Go is reduced under pathological loads of A beta, 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.
Shaked
Gideon M
GM
Department of Neurosciences, University of California San Diego, La Jolla, CA 92093-0624, USA.
Chauv
Stephanie
S
Ubhi
Kiren
K
Hansen
Lawrence A
LA
Masliah
Eliezer
E
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans
D016564:Amyloid beta-Protein Precursor; D019204:GTP-Binding Proteins; D002118:Calcium