Potential neurotoxic activity of diverse molecules released by microglia

Microglia are the professional immune cells of the brain, which support numerous physiological processes. One of the defensive functions provided by microglia involves secretion of cytotoxins aimed at destroying invading pathogens. It is also recognized that the adverse activation of microglia in diseased brains may lead to secretion of cytotoxic molecules, which could be damaging to the surrounding cells, including neurons. Several of these toxins, such as reactive oxygen and nitrogen species, L-glutamate, and quinolinic acid, are widely recognized and well-studied. This review is focused on a structurally diverse group of less-established microglia neurotoxins, which were selected by applying the two criteria that these molecules 1) can be released by microglia, and 2) have the potential to be directly harmful to neurons. The following 11 molecules are discussed in detail: amyloid beta peptides (Aβ); cathepsin (Cat)B and CatD; C-X-C motif chemokine ligand (CXCL)10 and CXCL12 (5-67); high mobility group box (HMGB)1; lymphotoxin (LT)-α; matrix metalloproteinase (MMP)-2 and MMP-9; platelet-activating factor (PAF); and prolyl endopeptidase (PEP). Molecular mechanisms of their release by microglia and neurotoxicity, as well as available evidence implicating their involvement in human neuropathologies are summarized. Further studies on several of the above molecules are warranted to confirm either their microglial origin in the brain or direct neurotoxic effects. In addition, investigations into the differential secretion patterns of neurotoxins by microglia in response to diverse stimuli are required. This research could identify novel therapeutic targets for neurological disorders involving adverse microglial activation.