Title:Putative Involvement of Endocrine Disruptors in the Alzheimer's Disease Via the Insulin-Regulated Aminopeptidase/GLUT4 Pathway
Volume: 19
Issue: 7
Author(s): María Jesús Ramírez-Expósito, Jose Manuel Martínez-Martos, Vanesa Cantón-Habas and María del Pilar Carrera-González*
Affiliation:
- Department of Health Sciences, Experimental and Clinical Physiopathology Research Group, Faculty of Experimental and Health Sciences, University of Jaen, E-23071 Jaen,Spain
Keywords:
Alzheimer's Disease, estrogens, endocrine disruptors, diabetes, insulin-regulated aminopeptidase, glucose
transporter 4.
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 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.
