ansgene with the addition of the Arctic mutation; all three lines are in the same C57Bl/6 genetic background. A comparison of TgArc48 and TgArc6 mice suggests that APP levels influence A oligomer formation: although these two lines carry the same APP purchase Aphrodine transgene in the same genetic background, TgArc48 mice express six times more APP and three times more A 56 than do TgArc6 mice. Further, comparing TgArc mice to hAPP-J20 mice suggests that the fibrillogenicity of the A peptides also influences the oligomer profile: the lines bearing the Arctic mutation generate approximately half the amount of A 56, normalized to APP levels, as does the hAPP-J20 line. Cheng and colleagues hypothesized that accelerating the formation of fibrils, by inclusion of the Arctic mutation, may lower the globular A species either by diverting monomers in a limiting pool away from the formation of globular assemblies, or by sequestering the globular assemblies directly into fibrils. The APP transgene in rTg9191 mice is similar to that in hAPP-J20 mice in that it contains the Swedish mutation that increases production PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19786614 of all forms of A, as well as an additional mutation in rTg9191) that shifts APP processing towards A42 . However, hAPP-J20 mice generate A 56, while rTg9191 mice do not. At this time, we can only speculate about which factors account for the different oligomer profiles observed in these two lines. Not only do rTg9191 and hAPP-J20 mice differ in genetic background, but also in the construction 14 / 26 Characterizing a Model of -Amyloid Toxicity of the APP transgene. As described here, rTg9191 mice are bi-genic, with the CaMKII promoter driving expression of the tetracycline transactivator in excitatory neurons of the forebrain, while the responder consists of cDNA encoding the 695-amino acid isoform of APP. By contrast, hAPP-J20 mice carry an APP mini-gene driven by the platelet-derived growth factor promoter. Notably, the two lines differ in the amount of A produced, in an age-dependent manner. At younger ages, steady-state levels of soluble A40 and A42 are comparable in hAPP-J20 and rTg9191 mice, but in mice greater than a year of age, levels of A peptides in rTg9191 mice greatly exceed those measured in hAPP-J20 mice. In addition to examining plaque-associated neuropathology, we also evaluated the relevance of our novel model to AD and several other mouse models of AD by quantifying and comparing dense-core plaque load 
in brain parenchyma. We observed that the density of neuritic plaques PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19785045 in rTg9191 mice was comparable to that in AD brains, whereas in some other mouse model systems, such as Tg85 and Tg6799, plaque loads were substantially greater than in AD. In summary, we have developed rTg9191 mice, a novel regulatable APP transgenic model that specifically produces fibrillar A assemblies. This unique feature allows studying the neurological effects of fibrillar A assemblies in situ, including the effects of such assemblies on cognition and plaque-associated neuropathology. Further, the regulatable property of the model allows temporal modulation of APP expression and A production. This feature enables studies of the interactions of A with age-related factors and, of particular clinical relevance, studies of the persistence of A-triggered pathology following reductions in A production. Materials and Methods Generation of rTg9191 mice Our methods for generating rTg9191 mice utilized a binary system of responder and activator transgenes. Mice expressin