Glutamate, Immune Cells and Alzheimer’s Disease: An Attempt to Link the Triad

Abstract Glutamate (Glu), although the main excitatory neurotransmitter (NT) of the central nervous system (CNS), evidence recognizes its role in influencing immune cell function and activation, including cytokine production, cell proliferation, migration, and survival. Importantly, dysregulation of Glu homeostasis has been implicated in the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, neuronal loss and neuroinflammation. This review synthesizes current evidence on the biochemistry of the glutamatergic synapse, as well as the expression and signaling of Glu receptors (GluRs) in human immune cells. Furthermore, it examines two major hypotheses of AD pathogenesis —the glutamatergic and the neuroimmune hypothesis— and proposes a unified glutamatergic–neuroimmune framework. In this model, disrupted glutamatergic signaling at the neuron–glia–immune interface may represent a central contributor to AD pathology. Understanding the glutamatergic–neuroimmune axis may provide novel insights into therapeutic strategies targeting neuroimmune modulation in AD.