Endogenous Proteins Controlling Amyloid β-Peptide Polymerization

We report that certain plasma proteins, at physiological concentrations, are potent inhibitors of amyloid β-peptide (Aβ) polymerization. These proteins are also present in cerebrospinal fluid, but at low concentrations having little or no effect on Aβ. Thirteen proteins representing more than 90% of the protein content in plasma and cerebrospinal fluid were studied. Quantitatively, albumin was the most important protein, representing 60% of the total amyloid inhibitory activity, followed by α 1 -antitrypsin and immunoglobulins A and G. Albumin suppressed amyloid formation by binding to the oligomeric or polymeric Aβ, blocking a further addition of peptide. This effect was also observed when the incorporation of labeled Aβ into genuine β-amyloid in tissue section was studied. The Aβ and the anti-diabetic drug tolbutamide apparently bind to the same site on albumin. Tolbutamide displaces Aβ from albumin, increasing its free concentration and enhancing amyloid formation. The present results suggest that several endogenous proteins are negative regulators of amyloid formation. Plasma contains at least 300 times more amyloid inhibitory activity than cerebrospinal fluid. These findings may provide one explanation as to why β-amyloid deposits are not found in peripheral tissues but are only found in the central nervous system. Moreover, the data suggest that some drugs that display an affinity for albumin may enhance β-amyloid formation and promote the development of Alzheimer’s disease.