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, Dutch type (HCHWA-D), is an autosomal dominant disorder caused by the Dutch mutation (E693Q) in the beta-amyloid precursor protein. This mutation produces an aberrant amyloid beta (Abeta) species (AbetaE22Q) 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 Abeta40 and Abeta42, with a high Abeta40/Abeta42 ratio. In Western blotting of cerebral microvessel fractions isolated from the brains, both wild-type and Dutch-type Abeta40 were observed as major species. Reverse-phase HPLC-mass spectrometric analysis of the fractions revealed both wild-type and Dutch-type Abeta38 as the other main components of the vascular amyloid. Moreover, we detected peaks corresponding to Dutch-type Abeta42 but not to wild-type Abeta42. These results suggest a pathogenic role for the mutant Abeta42 in addition to the mutant Abeta40 in the cerebral amyloid angiopathy of HCHWA-D.
Nishitsuji
Kazuchika
K
Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan.
Tomiyama
Takami
T
Ishibashi
Kenichi
K
Kametani
Fuyuki
F
Ozawa
Kazuharu
K
Okada
Ryota
R
Maat-Schieman
Marion L
ML
Roos
Raymund A C
RA
Iwai
Kazuhiro
K
Mori
Hiroshi
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D001808:Blood Vessels / Q000378:metabolism*; D002531:Cerebellum / Q000473:pathology*; D028243:Cerebral Amyloid Angiopathy, Familial / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)