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