Putative Involvement of Endocrine Disruptors in the Alzheimer's Disease Via the Insulin-Regulated Aminopeptidase/GLUT4 Pathway

It has been well established that there is a connection between type II diabetes (DMTII) and Alzheimer's disease (AD). In fact, the increase in AD incidence may be an emerging complication of DMTII. Both pathologies are related to estradiol (E-2) exposure; on the one hand, estrogen receptors (ER) are emerging as important modulators of glucose homeostasis through beta-pancreatic cell function; on the other hand, brain bioenergetic and cognitive deficits have been related to the down regulation of brain ERs, contributing to women ageing and AD susceptibility, both related to the reduction in estradiol levels and the deficits in brain metabolism. Here we discuss that environmental contaminants with estrogenic capacity such as bisphenol A (BPA) could develop pharmacological effects similar to those of E-2, which could affect beta-pancreatic cell function by increasing the biosynthesis of glucose-induced insulin after extranuclear ER binding. BPA-induced hyperinsulinemia would promote the translocation of glucose transporter 4 (GLUT4), which is located next to insulin-regulated aminopeptidase (IRAP) in intracellular vesicles. In insulin-responsive tissues, IRAP and GLUT 4 are routed together to the cell surface after insulin stimulation. IRAP is also the angiotensin IV (AngIV) receptor, and AngIV associates the brain renin-angiotensin system (bRAS) with AD, since AngIV is related to learning, memory, emotional responses, and processing of sensory information not only through its inhibitory effect on IRAP but also through the stimulation of glucose uptake by increasing the presence of IRAP/GLUT4 at the cell surface. Thus, the IRAP/GLUT4 pathway is an emerging target for pharmacological intervention against AD.

Automated summary

There is a connection between type II diabetes and Alzheimer's disease, both related to estradiol exposure and affecting glucose homeostasis. Environmental contaminants such as BPA could impact beta-pancreatic cell function similar to estradiol, potentially influencing the development of Alzheimer's disease. The pathway involving IRAP/GLUT4 is emerging as a target for pharmacological intervention against AD.