Ultrastructural evidence of early non-fibrillar Aβ42 in the capillary basement membrane of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type

The C-terminal profile and ultrastructure of small and presumably early capillary amyloid β protein (Aβ) deposits were investigated in four patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type. The C terminus of the 40 (Aβ40) or the 42 (Aβ42) amino acid form of Aβ was gold labeled in serial, ultrathin sections on glass slides for reflection contrast microscopy and on grids for electron microscopy. In all studied subjects, reflection contrast microscopy revealed capillaries with focal Aβ42 immunolabeling in the absence of Aβ40 labeling. In the adjacent electron microscopic section, Aβ42 labeling was confined to the capillary basement membrane. The majority of Aβ42+40– deposits showed no amyloid fibrils. Aβ42+40– deposits were sometimes observed in an unremarkable basement membrane but usually showed increased electron density and reticular structures. A small subset of Aβ42+40– deposits with basement membrane changes showed few amyloid fibrils. Aβ42+40+ capillary deposits always showed definite fibrils and were larger than Aβ42+40– capillary deposits. The present findings suggest that in capillaries the accumulation and subsequent polymerization of Aβ42, possibly in conjunction with basement membrane changes, precedes the definite fibril formation with Aβ40.