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alpha-2-macroglobulin, also known as α2-macroglobulin (α2M and A2M), is a protein abundant in the plasma of vertebrates and several invertebrates. A2M is an evolutionarily conserved arm of the innate immune system. It also mediates the proliferation of T cells and macrophages. A2M acts as a nonspecific protease inhibitor involved in the host defense mechanism that inactivates both endogenous and exogenous proteases, including trypsin, thrombin and collagenase. Even though A2M is produced predominantly by the liver, it may also be expressed in the reproductive tract, heart, and brain, and may have important roles in many physiological processes and medical illnesses including Alzheimer’s disease.