␣ 2 -Macroglobulin (␣ 2 M) and its receptor, low density lipoprotein receptor-related protein (LRP), function together to facilitate the cellular uptake and degradation of -amyloid peptide (A). In this study, we demonstrate that A binds selectively to ␣ 2 M that has been induced to undergo conformational change by reaction with methylamine. Denatured ␣ 2 M subunits, which were immobilized on polyvinylidene difluoride membranes, bound A, suggesting that ␣ 2 M tertiary and quaternary structure are not necessary. To determine whether a specific sequence in ␣ 2 M is responsible for A binding, we prepared and analyzed defined ␣ 2 M fragments and glutathione S-transferase-␣ 2 M peptide fusion proteins. A single sequence, centered at amino acids (aa) 1314 -1365, was identified as the only major A-binding site. Impor Accumulation of -amyloid peptide (A and A ) 1 in the brain plays a central role in the development and progression of Alzheimer's disease (AD) (1). Mutations in -amyloid precursor protein (APP), which result in increased production of A, are associated with autosomal dominant forms of familial AD in humans (2-4). Mutated forms of human APP may also induce changes consistent with AD when expressed as transgenes in mice (5-8). Furthermore, immunization with A (1-42) prevents progression of AD in animal model systems and may reverse symptoms by promoting resorption of A-containing plaques (9, 10). These results suggest that A accumulation in the brain is a dynamic and reversible process. Proteins other than antibodies with the capacity to bind A and promote its catabolism may influence disease progression.␣ 2 -Macroglobulin (␣ 2 M) is a 718-kDa homotetrameric glycoprotein, which is well characterized as an extracellular proteinase inhibitor (11) and as a carrier of specific growth factors, including transforming growth factor- (TGF-) and nerve growth factor- (NGF-) (12, 13). At least two separate polymorphisms in the A2M gene may be associated with increased risk of late-onset AD. The first involves a region within intron 17, at the 5Ј splice acceptor site for exon 18 (14). This exon is important because it encodes part of the bait region, where proteinases initiate reaction with ␣ 2 M by cleaving susceptible peptide bonds (15,16), and a segment of the growth factor binding sequence (17)(18)(19). In the second A2M gene polymorphism, Val-1000 is replaced by Ile (20). The linkage of A2M gene polymorphisms to late-onset AD remains incompletely understood, because the original observations have been confirmed in only a limited number of populations (21-25) and because there is no molecular explanation regarding how A2M gene mutations may affect ␣ 2 M structure, function, and expression.␣ 2 M is expressed by microglia, which accumulate near amyloid plaques (26). Thus, locally synthesized ␣ 2 M may affect AD progression by regulating the activity of various proteinases or by binding important growth factors. The previously demonstrated ability of ␣ 2 M to bind and neutralize the activity of TGF-...