Abstract

Considered relevant during allergy responses, numerous observations have also identified mast cells (MCs) as critical effectors during the progression and modulation of several neuroin-flammatory conditions, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). MC granules contain a plethora of constituents, including growth factors, cytokines, chemo-kines, and mitogen factors. The release of these bioactive substances from MCs occurs through distinct pathways that are initiated by the activation of specific plasma membrane receptors/channels. Here, we focus on hemichannels (HCs) formed by connexins (Cxs) and pannexins (Panxs) proteins, and we described their contribution to MC degranulation in AD, ALS, and harmful stress condi-tions. Cx/Panx HCs are also expressed by astrocytes and are likely involved in the release of critical toxic amounts of soluble factors—such as glutamate, adenosine triphosphate (ATP), complement component 3 derivate C3a, tumor necrosis factor (TNFα), apoliprotein E (ApoE), and certain miR-NAs—known to play a role in the pathogenesis of AD, ALS, and other neurodegenerative disorders. We propose that blocking HCs on MCs and glial cells offers a promising novel strategy for ameliorating the progression of neurodegenerative diseases by reducing the release of cytokines and other pro-inflammatory compounds.