Modulation of fibrin assembly and polymerization by the β-amyloid of Alzheimer's disease

Vascular deposition of amyloid beta protein (AβP) is associated with recurrent intracerebral hemorrhages in certain disease states. Based upon these findings, we studied the effect of AβP on fibrin (Fn) formation and fibrinolysis. We utilized electron microscopy and light scattering studies to examine alterations in the nature of the Fn clots obtained in the presence of the amyloid of Alzheimer's disease (AD), AβP 1-40. Electron microscopic analysis revealed a network of Fn and amyloid fibers formed in the presence of AβP with significantly decreased lateral Fn-Fn interactions. Additional evidence for the assembly of an altered Fn matrix was obtained from kinetic assays that included fibrinogen (Fg), plasminogen, tissue-type plasminogen activator, and thrombin, in the presence of a fibril-forming peptide derived from AβP (AβP 34-42). Turbidometric analysis of Fn clots showed that thrombin-treated Fg forms increasingly denser and more compact Fn fibers in the presence of increasing molar equivalents of AβP 1-40. This conclusion was based upon the observed increases in the mass-to-length ratios, fiber radii, fiber densities, and the calculated number of Fn monomers per fiber cross-section. These results taken together suggest that amyloid forming peptides and proteins of AD significantly alter the nature of the Fn obtained in their presence.