Cerebral vascular accumulation of Dutch-type Abeta42, but not wild-type Abeta42, in hereditary cerebral hemorrhage with amyloidosis, Dutch type.

[hereditary cerebral hemorrhage with amyloidosis]

Hereditary cerebral hemorrhage with amyloidosis , Dutch type (HCHWA-D ), is an autosomal dominant disorder caused by the Dutch mutation (E 693 Q ) in the beta -amyloid precursor protein . This mutation produces an aberrant amyloid beta (Abeta ) species (AbetaE 22 Q ) and causes severe meningocortical vascular Abeta deposition . We analyzed the Abeta composition of the vascular amyloid in the brains of HCHWA-D patients . Immunohistochemistry demonstrated that the vascular amyloid contained both Abeta 40 and Abeta 42 , with a high Abeta 40 /Abeta 42 ratio . In Western blotting of cerebral microvessel fractions isolated from the brains , both wild-type and Dutch -type Abeta 40 were observed as major species . Reverse-phase HPLC-mass spectrometric analysis of the fractions revealed both wild-type and Dutch -type Abeta 38 as the other main components of the vascular amyloid . Moreover , we detected peaks corresponding to Dutch -type Abeta 42 but not to wild-type Abeta 42 . These results suggest a pathogenic role for the mutant Abeta 42 in addition to the mutant Abeta 40 in the cerebral amyloid angiopathy of HCHWA-D .