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

Abstract

: 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 (E2) exposure; on the one hand, estrogen receptors (ER) are emerging as important modulators of glucose homeostasis through ß-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 E2, which could affect ß-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 reninangiotensin 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 the pharmacological intervention against AD.

Estrogen and Glycemic Homeostasis: The Fundamental Role of Nuclear Estrogen Receptors ESR1/ESR2 in Glucose Transporter GLUT4 Regulation

“…In addition to phytoestrogens, we should also consider another group of ESR1/2 ligands, selective estrogen receptor modulators (SERMs), which include a large group of environmental contaminants with a potential role to stimulate or inhibit estrogenic activity. In a recent review, putative involvement of endocrine disruptor bisphenol A in Alzheimer’s disease was proposed to involve impaired GLUT4 translocation in hippocampal neurons, although there is no evidence to support this suggestion [ 115 ].…”

Alzheimer Disease-Type 3 Diabetes: Traditional Review

“…Beyinde GLUT4'ün olduğu kanıtlanmış olsa da insülinin nöronal glukoz metabolizması katkısı henüz netlik kazanmamıştır. 5,36,41,[45][46][47] Beyinde sinaptik plastisite oluşmasında insülin ve insülin benzeri büyüme faktörü [insulin-like growth factor (IGF)] sinyal mekanizmaları önemlidir. İnsülin direnci ve IGF I/II eksikliğinde sinaptik ve nöronal plastisitede bozulmalar olmaktadır.…”