beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease

Abstract

Reinvestigation of the chemical structure of beta-amyloid peptide (A beta) deposits in the vascular tissue of Alzheimer disease brains revealed that the 42-residue form A beta-(1-42), rather than the more soluble A beta-(1-40) form, is the predominant peptide. Following removal of the surrounding tissue with SDS and collagenase, A beta was solubilized in formic acid and purified by Superose 12 chromatography. Peptides generated by enzymatic and chemical digestion of the A beta were purified by HPLC and characterized by amino acid analysis, sequence analysis, and mass spectrometry. In the leptomeningeal vessels, the average ratio of A beta-(1-42)/A beta-(1-40) was 58:42, whereas in the parenchymal vessels this ratio was 75:25. Interestingly, vascular A beta contains considerably less isomerized and racemized aspartyl residues than does neuritic plaque A beta, suggesting that the vascular amyloid is "younger." The discrete nature of the bands and spherical deposits of A beta associated with arterioles and capillaries, respectively, suggests that this amyloid arises from the vascular tissue itself. Increasing A beta deposition appears to lead to the distortion and occlusion of capillaries, which may contribute significantly to the pathology of Alzheimer disease.