E22Q-mutant Abeta peptide (AbetaDutch) increases vascular but reduces parenchymal Abeta deposition.
Patients that have hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) generate both wild-type beta-amyloid (Abetawt) and E22Q-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) APP23 mice were crossed with APPDutch mice. Although single-tg APP23 mice deposited Abetawt with aging, double-tg APP23/APPDutch mice co-deposited AbetaDutch (mainly AbetaDutch1-40) and Abetawt at twofold higher total Abeta levels. Vascular Abeta deposits and hemorrhages were twice as high in APP23/APPDutch mice compared with APP23 mice. Surprisingly, parenchymal Abeta deposition was reduced in the double-tg mice compared with the single-tg APP23 mice. Our findings suggest that AbetaDutch1-40 inhibits parenchymal amyloidosis but exacerbates vascular amyloid, hence explaining the compartment-specific distribution of cerebral amyloid in HCHWA-D patients.
Herzig
Martin C
MC
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller Strasse 27, D-72076 Tübingen, Germany.
Eisele
Yvonne S
YS
Staufenbiel
Matthias
M
Jucker
Mathias
M
D000368:Aged; D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics; D019943:Amino Acid Substitution; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000473:pathology*; D028243:Cerebral Amyloid Angiopathy, Familial / Q000235:genetics*; D002543:Cerebral Hemorrhage / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor