Biased agonism of Amylin receptor and its therapeutic implications in Alzheimer's disease

• Published in: The FASEB journal 2022-05, Vol.36 (S1), p.n/a
• Main Authors: Labrador, Luis, Corrigan, Rachel R., Casadesus, Gemma
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R6206

The pancreatic protein Amylin has biophysical properties similar to amyloid‐beta (Aβ), the main pathological hallmark of Alzheimer’s disease. Interestingly, while data support the potential pathogenic role of amylin in AD, others have shown that the administration of amylin or an amylin analog (pramlintide) improves function and pathology in murine models of AD. The amylin receptor is a widely expressed G‐protein coupled receptor expressed in cerebral vasculature, glia and neurons, however the study of amylin signaling is complicated by the fact that it signals through three different receptor subtypes which are also differentially expressed. Therefore, the goal of this work was to identify the how these different receptor subtypes respond to both agonism and antagonism and in the presence of binding at physiologically relevant levels (Aβ). We also sought to evaluate how these receptor subtypes regulated cellular aspects associated with T2D (glucose resistance). We used SH‐SY5Y (neuroblastoma) cells as an in vitro model, with overexpression of AMY1 and AMY3, treated with 4 different concentrations of Amylin (between 0.5‐20μM), with AB (5‐40μM), PRAM (0.5‐20μM) and AC187 (5‐20μM). Cell viability was determined by SytoxBlue. By western blot the differential activity of GSK3/AKT or PKA and ERK is detected. To observe breakdown of the β‐arrestin complex to the receptor, we performed co‐immunoprecipitation with AKT. We also determined the level of glucose resistance by 2DG fluorescence in animals treated under the above conditions. Preliminary results support the differential effects of these receptor subtypes on the evaluated cascades. This will allow us to clarify amylin receptor signaling mechanisms as well as the current conflicting data on its involvement in AD pathogenesis or neuroprotection.