To determine the most effective route of administration we performed pharmacokinetics studies

plaques are one of the pathological hallmarks of Alzheimer’s disease. A plaques can typically be classified as diffuse or dense-core types based on morphology and affinity for thioflavin S or Congo red. It is well established that, in the brains of AD patients and amyloid precursor protein transgenic mice, dense-core–but not diffuse–plaques are associated with varied forms of neuropathology, such as neuroinflammation, abnormal neuronal architecture, and hyperphosphorylation and misfolding of tau . However, recent studies suggest that soluble oligomeric assemblies of A are more likely responsible for AD pathogenesis. In AD patients or model organisms of the disease, A assumes multiple oligomeric forms, including but not limited to: A dimers, A 56, amylospheroids, and annular protofibrils. These brain-derived oligomers have been identified based on size and composition, and each has a unique spatial and temporal expression pattern. In addition, A assemblies have been characterized based on their immunoreactivity to conformation-selective antibodies–OC, which recognizes an epitope found in A fibrils and some soluble oligomers, and A11 which recognizes a mutually exclusive epitope found on other soluble oligomers . Understanding the Danoprevir biological activity neurological effects of each type of oligomer has been difficult, because numerous A assemblies often coexist within an individual brain. Here, we report the generation and characterization of a novel APP transgenic mouse model uniquely suited to study the neurological effects of fibrillar A aggregates in situ. These mice, which express a regulatable APP transgene, develop an amyloid plaque load similar to that of AD patients, and produce fibrillar A assemblies but negligible amounts of non-fibrillar oligomers. Results Expression and suppression of APP transgene We created a regulatable transgenic mouse line, rTg9191, modeling A pathology in AD. The rTg9191 mice harbor the 695 amino-acid isoform of human APP with the Swedish and London mutations that are linked to familial AD. Expression of APPNLI is driven by an interaction between the tetO promoter and the tetracycline-controlled transactivator, whose expression is driven by a calcium-calmodulin kinase II protomer. Transgene expression can be suppressed by doxycycline -mediated disruption of the tTA-tetO interaction. Western blot analyses of the membrane-enriched fraction of brain protein extracts showed that the rTg9191 line expresses APPNLI at a level four times that of endogenous mouse APP. Additionally, we found that the level of APPNLI remains constant with age and is two-thirds the transgenic APP level in Tg2576 mice. PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19783938 Administration of DOX to mice for 2 months resulted in an 87% reduction in the level of APPNLI expression. Regional expression pattern of APP transgene The expression of APPNLI in various brain regions was analyzed using LN27 and 6E10, two antibodies that recognize the N-terminus and A region of human APP, respectively. For both antibodies, APPNLI expression was observed in cerebral cortex, hippocampus, and olfactory bulb– but not PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19784385 in cerebellum; in addition, the level of expression was qualitatively similar in the cerebral cortex and hippocampus, but was lower in the olfactory bulb. This regional expression pattern of the transgene in rTg9191 mice is consistent with that seen in the rTg4510 and rTg3696AB lines, which share the same binary tet-off induction system as the rTg9191 line. 2 / 26 Characterizing a Model of -Amyloid Toxicity Fi