In:
The FEBS Journal, Wiley, Vol. 276, No. 10 ( 2009-05), p. 2736-2751
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1742-464X
,
1742-4658
DOI:
10.1111/ejb.2009.276.issue-10
DOI:
10.1111/j.1742-4658.2009.06997.x
Language:
English
Publisher:
Wiley
Publication Date:
2009
detail.hit.zdb_id:
2172518-4
SSG:
12
Bookmarklink
