BETA-AMYLOID-(1-42) IS A MAJOR COMPONENT OF CEREBROVASCULAR AMYLOID DEPOSITS - IMPLICATIONS FOR THE PATHOLOGY OF ALZHEIMER-DISEASE

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