E22Q-Mutant Aβ Peptide (AβDutch) Increases Vascular but Reduces Parenchymal Aβ Deposition

Patients that have hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) generate both wild-type beta-amyloid (A beta wt) and E22Q-mutant beta-amyloid (A beta Dutch). 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 A beta wt and A beta Dutch variants, transgenic (tg) APP23 mice were crossed with APPDutch mice. Although single-tg APP23 mice deposited A beta wt with aging, double-tg APP23/APPDutch mice co-deposited A beta Dutch (mainly A beta Dutch1-40) and A beta wt at two fold higher total A beta levels. Vascular A beta deposits and hemorrhages were twice as high in APP23/APPDutch mice compared with APP23 mice. Surprisingly, parenchy mal A beta deposition was reduced in the double-tg mice compared with the single-tg APP23 mice. Our findings suggest that A beta Dutch1-40 inhibits parenchymal amyloidosis but exacerbates vascular amyloid, hence explaining the compartment-specific distribution of cerebral amyloid in HCHWA-D patients. (Am J Pathol 2009,174:722-726- DOI: 10.2353/ajpath.2009.080790)