Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator

Alpha-macroglobulins are ancient proteins that include monomeric, dimeric, and tetrameric family members. In humans, and many other mammals, the predominant alpha-macroglobulin is alpha-2-macroglobulin (α ₂M), a tetrameric protein that is constitutively abundant in biological fluids (e.g., blood plasma, cerebral spinal fluid, synovial fluid, ocular fluid, and interstitial fluid). α ₂M is best known for its remarkable ability to inhibit a broad spectrum of proteases, but the full gamut of its activities affects diverse biological processes. For example, α ₂M can stabilise and facilitate the clearance of the Alzheimer's disease-associated amyloid beta (Aβ) peptide. Additionally, α ₂M can influence the signalling of cytokines and growth factors including neurotrophins. The results of several studies support the idea that the functions of α ₂M are uniquely regulated by hypochlorite, an oxidant that is generated during inflammation, which induces the native α ₂M tetramer to dissociate into dimers. This review will discuss the evidence for hypochlorite-induced regulation of α ₂M and the possible implications of this in neuroinflammation and neurodegeneration.