Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer's Disease.

Grzegorz A Czapski,Joanna B Strosznajder

doi:10.3390/ijms222111677

Abstract

The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer’s disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of microglial receptors regulates the immunological response of these cells, which in AD could be neuroprotective or neurotoxic. The novel research approaches revealed the complexity of microglial function, including the interplay with other cells during neuroinflammation and in the AD brain. The purpose of this review is to describe the role of several proteins and multiple receptors on microglia and neurons, and their involvement in a communication network between cells that could lead to different metabolic loops and cell death/survival. Our review is focused on the role of glutamatergic, GABAergic signaling in microglia–neuronal cross-talk in AD and neuroinflammation. Moreover, the significance of AD-related neurotoxic proteins in glutamate/GABA-mediated dialogue between microglia and neurons was analyzed in search of novel targets in neuroprotection, and advanced pharmacological approaches.

Highlights

Alzheimer’s disease (AD) is the major cause of cognitive impairment and dementia, which affects about 50 million people, and its prevalence was estimated to triple worldwide by 2050 [1]
The recent hypothesis of homeostasis network collapse suggests that the imbalance between excitation and inhibition in the central nervous system (CNS), leading to dysregulation of neuronal networks, might be an exacerbating or even causative factor in the etiopathology of AD [83,84,85,86]
gamma-aminobutyric acid (GABA) is converted to glutamine, and it is transferred back to the neurons and converted to glutamate, postsynaptic), and metabotropic GABAB receptors, and to microglial GABAA/B

Summary

Introduction

Alzheimer’s disease (AD) is the major cause of cognitive impairment and dementia, which affects about 50 million people, and its prevalence was estimated to triple worldwide by 2050 [1]. Alternative hypotheses proposed other possible AD initiating factors, such as metabolic imbalance, infections, and toxins [2,6,7] These factors, together with Aβ peptides and other proteins with altered conformation, affect several neurotransmitters and growth factors-dependent signaling pathways and communication networks between neurons, microglia, astrocytes, and other cells, leading to synaptic apoptosis and neuronal death. We will focus on the role of glutamatergic and GABAergic neurotransmitter systems in cross-talk between these cells in the brain, and on its impairment in the progression of AD. Based on this knowledge, the novel pharmacological therapeutic approaches will be presented

The Role of Microglia in the Brain

Glutamatergic Signaling in Microglia–Neuron Communication in AD

Findings

Concluding Remarks and Future Challenges