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, are potent inhibitors of amyloid beta-peptide (Abeta) polymerization. These proteins are also present in cerebrospinal fluid, but at low concentrations having little or no effect on Abeta. 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 alpha1-antitrypsin and immunoglobulins A and G. Albumin suppressed amyloid formation by binding to the oligomeric or polymeric Abeta, blocking a further addition of peptide. This effect was also observed when the incorporation of labeled Abeta into genuine beta-amyloid in tissue section was studied. The Abeta and the anti-diabetic drug tolbutamide apparently bind to the same site on albumin. Tolbutamide displaces Abeta 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 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 that display an affinity for albumin may enhance beta-amyloid formation and promote the development of Alzheimer's disease.
Bohrmann
B
B
F. Hoffmann-La Roche AG, Pharma Division, Preclinical Research, CH-4070, Basel, Switzerland.
Tjernberg
L
L
Kuner
P
P
Poli
S
S
Levet-Trafit
B
B
Näslund
J
J
Richards
G
G
Huber
W
W
Döbeli
H
H
Nordstedt
C
C
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001665:Binding Sites; D019921:Biotinylation; D001798:Blood Proteins / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism*; D002556:Cerebrospinal Fluid Proteins / Q000378:metabolism*; D046508:Culture Techniques; D006801:Humans; D008854:Microscopy, Electron; D011108:Polymers / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D012709:Serum Albumin / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D001798:Blood Proteins; D002556:Cerebrospinal Fluid Proteins; D011108:Polymers; D012709:Serum Albumin; D014044:Tolbutamide