E22Q-mutant Abeta peptide (AbetaDutch) increases vascular but reduces parenchymal Abeta deposition.

[hereditary cerebral hemorrhage with amyloidosis]

Patients that have hereditary cerebral hemorrhage with amyloidosis -Dutch type (HCHWA-D ) generate both wild-type beta -amyloid (Abetawt ) and E 22 Q -mutant beta -amyloid (AbetaDutch ). Postmortem analysis of HCHWA-D brains reveals severe cerebral amyloid angiopathy with very little parenchymal amyloid deposition . To investigate amyloidosis in the presence of both Abetawt and AbetaDutch variants , transgenic (tg ) APP 23 mice were crossed with APPDutch mice . Although single -tg APP 23 mice deposited Abetawt with aging , double -tg APP 23 /APPDutch mice co -deposited AbetaDutch (mainly AbetaDutch 1 -40 ) and Abetawt at twofold higher total Abeta levels . Vascular Abeta deposits and hemorrhages were twice as high in APP 23 /APPDutch mice compared with APP 23 mice . Surprisingly , parenchymal Abeta deposition was reduced in the double -tg mice compared with the single -tg APP 23 mice . Our findings suggest that AbetaDutch 1 -40 inhibits parenchymal amyloidosis but exacerbates vascular amyloid , hence explaining the compartment-specific distribution of cerebral amyloid in HCHWA-D patients .