Herzig et al.47 developed transgenic lines that expressed human wild-type APP, APP-Dutch, or APP-Dutch crossed with a PS1 FAD mutant. These lines exhibited various Aβ40/Aβ42 ratios, with the APP-Dutch ratio higher than the wild-type APP ratio, which was in turn greater than the APP-Dutch/PS1 ratio. The high Aβ40/Aβ42 ratio in the APP-Dutch mice resulted in extensive vascular amyloid deposition with essentially no parenchymal deposition. By contrast, APP-Dutch/PS1 mice with about half the Aβ40/Aβ42 ratio of APP-Dutch mice developed parenchymal plaques with little vascular deposition, and wild-type APP mice with intermediate Aβ40/Aβ42 ratios had mixed parenchymal and vascular deposition. Thus, although Aβ42 may be needed as a seed for amyloid deposition in either compartment, these studies suggest that Aβ40 promotes vascular deposition, whereas Aβ42 shifts deposition toward parenchymal amyloid. Other studies72 have, however, found that transgenic mice harboring a distinct 693 mutation (E693G/Arctic) combined with APP-Swedish and APP-Indiana mutations develop prominent parenchymal plaque deposits with little congophilic angiopathy despite high Aβ40/Aβ42 ratios. Thus, some property of mutations at the 693 site, besides their effect on Aβ40/Aβ42 ratios, also appears to influence parenchymal deposition versus vascular deposition.
