With more people reaching an advanced age in modern society, there is a growing need
for strategies to slow down age-related neuropathology and loss of cognitive functions, which are a
hallmark of Alzheimer's disease. Neuroprotective drugs and candidate drug compounds target one
or more processes involved in the neurodegenerative cascade, such as excitotoxicity, oxidative
stress, misfolded protein aggregation and/or ion dyshomeostasis. A growing body of research shows
that a G-protein coupled zinc (Zn2+) receptor (GPR39) can modulate the abovementioned processes.
Zn2+itself has a diverse activity profile at the synapse, and by binding to numerous receptors, it
plays an important role in neurotransmission. However, Zn2+ is also necessary for the formation of
toxic oligomeric forms of amyloid beta, which underlie the pathology of Alzheimer’s disease. Furthermore,
the binding of Zn2+ by amyloid beta causes a disruption of zincergic signaling, and recent
studies point to GPR39 and its intracellular targets being affected by amyloid pathology.
In this review, we present neurobiological findings related to Zn2+ and GPR39, focusing on its signaling
pathways, neural plasticity, interactions with other neurotransmission systems, as well as on
the effects of pathophysiological changes observed in Alzheimer's disease on GPR39 function.
Direct targeting of the GPR39 might be a promising strategy for the pharmacotherapy of zincergic
dyshomeostasis observed in Alzheimer’s disease. The information presented in this article will
hopefully fuel further research into the role of GPR39 in neurodegeneration and help in identifying
novel therapeutic targets for dementia.