Amyloid beta-peptide polymerization studied using fluorescence correlation spectroscopy

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作   者：

Tjernberg LO.;  Bjorling S.;  Thyberg P.;  Thyberg J.;  Nordstedt C.;  Berndt KD.;  Terenius L.;  Rigler R.;  Pramanik A.; 

作者机构：

Dept Clin Neurosci;  Lab Biochem & Mol Pharmacol;  Karolinska Hosp;  Sweden;  S-17176 Stockholm;  Sect Drug Dependence Res;  .; 

关键词：

Missense mutations;  Amino-terminal fragment;  Fibril formation;  Aggregation properties;  Integral-equations;  Transgenic mice;  Polymerization;  In-vitro;  Amyloid beta-peptide;  Atomic-force microscopy;  Familial alzheimers-disease;  Precursor protein;  Alzheimer's disease;  Fluorescence correlation spectroscopy; 

期刊名称：

Chemistry & biology

i s s n：

1074-5521

年卷期：

1999 年 6 卷 1 期

页   码：

53-62

页   码：

摘   要：

Background: The accumulation of fibrillar deposits of amyloid beta-peptide (A beta) in brain parenchyma and cerebromeningeal blood vessels is a key step in the pathogenesis of Alzheimer's disease. In this report, polymerization of A beta was studied using fluorescence correlation spectroscopy (FCS), a technique capable of detecting small molecules and large aggregates simultaneously in solution. Results: The polymerization of A beta dissolved in Tris-buffered saline, pH 7.4, occurred above a critical concentration of 50 mu M and proceeded from monomers/dimers into two discrete populations of large aggregates, without any detectable amount of oligomers. The aggregation showed very high cooperativity and reached a maximum after 40 min, followed by an increase in the amount of monomers/dimers and a decrease in the size of the large aggregates. Electron micrographs of samples prepared at the time for maximum aggregation showed a mixture of an amorphous network and short diffuse fibrils, whereas only mature amyloid fibrils were detected after one day of incubation. The aggregation was reduced when A beta was incubated in the presence of A beta ligands, oligopeptides previously shown to inhibit fibril formation, and aggregates were partly dissociated after the addition of the ligands. Conclusions: The polymerization of A beta is a highly cooperative process in which the formation of very large aggregates precedes the formation of fibrils. The entire process can be inhibited and, at least in early stages, partly reversed by A beta ligands.