IGF1R/ARRB1 Mediated Regulation of ERK and cAMP Pathways in Response to Aβ Unfolds Novel Therapeutic Avenue in Alzheimer's Disease.

Abstract

IGF1R/INSR signaling is crucial for understanding Alzheimer's disease (AD) and may aid in the development of potent therapeutic strategies. This study investigated the expression and activity of these receptors and their potential to form functional hybrids in response to amyloid beta (Aβ). IGF1R, INSR, and ARRB1 were found to be upregulated in AD. The propensity for functional hybrid formation was also greater in the presence of Aβ. The association of IGF1R with ARRB1 reached a maximum at 60 min of Aβ treatment, which coincided with increased pERK activity at approximately the same time, indicating the importance of this association in pERK regulation. Knocking down IGF1R, INSR, and ARRB1 independently reduced cAMP, whereas overexpressing IGF1R significantly increased cAMP. Knocking down ARRB1 in IGF1R-overexpressing cells led to a reduction in cAMP, indicating that the interaction of ARRB1 and IGF1R possibly contributes to cAMP dysregulation. Since cAMP plays a crucial role in cognition and memory, alterations in cAMP after receptor hybridization could be significant in AD. Additionally, we noted hyperactivation of MAPK, which is associated with aberrant cellular activity, transcriptional control, and stress pathways. This finding highlights the importance of IGF1R and INSR dysregulation, which plays a major role in addition to conventional RTK signaling through multiple pathways. Here, we focused on the ARRB1 and IGF1R interaction and showed that picropodophyllin (PPP), an IGF1R-specific inhibitor, blocks this interaction and alters the ERK and cAMP status under disease conditions. Cell viability studies further revealed that the PPP substantially improved cell viability in the presence of Aβ. This highlights the role of the PPP in regulating these cascades and opens the arena for further therapeutic development for AD.