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
Direct targeting of the GPR39 might be a promising strategy for 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.