Endogenous proteins controlling amyloid beta-peptide polymerization - Possible implications for beta-amyloid formation in the central nervous system and in peripheral tissues

We report that certain plasma proteins, at physiological concentrations, ar e potent inhibitors of amyloid beta-peptide (A beta) polymerization. These proteins are also present in cerebrospinal fluid, but at low concentrations having little or no effect on A beta. Thirteen proteins representing more than 90% of the protein content in plasma and cerebrospinal fluid were stud ied. Quantitatively, albumin was the most important protein, representing 6 0% of the total amyloid inhibitory activity, followed by alpha(1)-antitryps in and immunoglobulins A and G, Albumin suppressed amyloid formation by bin ding to the oligomeric or polymeric A beta, blocking a further addition of peptide. This effect was also observed when the incorporation of labeled A beta into genuine beta-amyloid in tissue section was studied. The A beta an d the anti-diabetic drug tolbutamide apparently bind to the same site on al bumin. Tolbutamide displaces A beta from albumin, increasing its free conce ntration and enhancing amyloid formation. The present results suggest that several endogenous proteins are negative regulators of amyloid formation. P lasma contains at least 300 times more amyloid inhibitory activity than cer ebrospinal fluid. These findings may provide one explanation as to why beta -amyloid deposits are not found in peripheral tissues but are only found in the central nervous system. Moreover, the data suggest that some drugs tha t display an affinity for albumin may enhance beta-amyloid formation and pr omote the development of Alzheimer's disease.