Alzheimer’s disease (AD) is the most reoccurring type of dementia, and remains incurable. Much work has been done to investigate the connections between AD development, type 2 diabetes and insulin receptor signaling abnormalities. Full length amyloid precursor protein (flAPP) is a large transmembrane protein that has significant physiological activities including in utero fetal development. Alpha secretase enzymes cleave flAPP, producing secreted amyloid precursor protein alpha (sAPPα), which has neuroprotective properties, including protection against neuronal apoptosis as well as the induction of neuronal outgrowth. There is no known dedicated receptor for the physiological action of sAPPα. Our data suggest that the physiological actions of sAPPα are a result of the physical interaction between sAPPα and the neuronal insulin receptor. We have shown that sAPPα phosphorylates, and thus activates, the neuronal insulin receptor as well as specific downstream proteins, including insulin receptor substrate (IRS), and protein kinase B (Akt). We have also shown that the observed interaction between sAPPα and neuronal insulin receptors is physical and that sAPPα competes with insulin for the insulin binding site.
These findings may have implications for therapies aimed at slowing down the progression of AD through the activation of the insulin receptor pathway, since in neurons, insulin and the insulin receptor pathway are critical to the neuronal health and plasticity.
| Identifer | oai:union.ndltd.org:MANITOBA/oai:mspace.lib.umanitoba.ca:1993/23418 |
| Date | 09 April 2014 |
| Creators | Aboud, Zaid A. |
| Contributors | Glazner, Gordon (Pharmacology and Therapeutics), Fernyhough, Paul (Pharmacology and Therapeutics) Rastegar, Mojgan (Biochemistry and Medical Genetics) Kong, Jiming (Human Anatomy and Cell Science) |
| Source Sets | University of Manitoba Canada |
| Detected Language | English |
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