Modulatory effects of α7 nAChRs on the immune system and its relevance for CNS disorders

Abstract

The clinical development of selective alpha-7 nicotinic acetylcholine receptor (α7 nAChR) agonists has hitherto been focused on disorders characterized by cognitive deficits (e.g., Alzheimer's disease, schizophrenia). However, α7 nAChRs are also widely expressed by cells of the immune system and by cells with a secondary role in pathogen defense. Activation of α7 nAChRs leads to an anti-inflammatory effect. Since sterile inflammation is a frequently observed phenomenon in both psychiatric disorders (e.g., schizophrenia, melancholic and bipolar depression) and neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, and multiple sclerosis), α7 nAChR agonists might show beneficial effects in these central nervous system disorders. In the current review, we summarize information on receptor expression, the intracellular signaling pathways they modulate and reasons for receptor dysfunction. Information from tobacco smoking, vagus nerve stimulation, and cholinesterase inhibition is used to evaluate the therapeutic potential of selective α7 nAChR agonists in these inflammation-related disorders.

Keywords: Autism; CREB; Dyskinesia; GSK3; Lithium; Nrf2; Suicide.

Fig. 1

Schematic anti-inflammatory signaling pathways activated by nAChR α7. Stimulation of nAChR α7 activates Jak2 leading to inhibition of NFκB and GSK3 but also to CREB activation. A separate signaling cascade involves activation of PKA and AKT enabling the nuclear translocation of Nrf2 (NFE2L2), which drives expression of HMOX1 (HO-1). This pathway elicits potent anti-inflammatory and neuroprotective effects

Fig. 2

Microglia cells play a role in eradication of invading microorganisms and in removal of debris. During these processes, the cells adapt specialized phenotypes (M1 and M2-like, respectively). During the respiratory burst, labile oxygen products are formed that oxidize microbial proteins and nucleic acids, but also oxidize the essential cofactor for monoamine synthesis, tetrahydrobiopterin. Sterile neuroinflammation is a common observation in neurological and psychiatric disorders. Acetylcholine, acting via α7 nAChRs, promotes M2-polarization. As such, it reduces neuroinflammation, while promoting phagocytosis. M2-polarized microglia cells not only produce neurotrophins and anti-inflammatory cytokines, they also effectively phagocytose and catabolize Aβ. α7 nAChR agonists are expected to improve neurological and psychiatric disorders via inhibition of neuroinflammation, to restore tetrahydrobiopterin levels (improve mood symptoms) and to provide neuroprotection

Fig. 3

During aging the polarization of microglia gradually shifts towards the M1 phenotype. Diminution of M2 polarization presumably has negative consequences for Aβ catabolism. When extracellular Aβ levels increase, several positive feedback loops are triggered that ultimately lead to the demise of cholinergic neurons. Activation of α7 nAChRs counteracts the loss of the M2 phenotype. α7 nAChR agonists may furthermore compete with Aβ at (mitochondrial?) nicotinic α7β2 receptors. Treatment with α7 nAChR agonists might therefore delay the demise of cholinergic neurons, and thus delay the onset of dementia