title: Biochemical and behavioral characterization of the double transgenic mouse model (APPswe/PS1dE9) of Alzheimer's disease.
abstract: OBJECTIVE The double transgenic mouse model (APPswe/PS1dE9) of Alzheimer's disease (AD) has been widely used in experimental studies. β-Amyloid (Aβ) peptide is excessively produced in AD mouse brain, which affects synaptic function and the development of central nervous system. However, little has been reported on characterization of this model. The present study aimed to characterize this mouse AD model and its wild-type counterparts by biochemical and functional approaches. METHODS Blood samples were collected from the transgenic and the wild-type mice, and radial arm water maze behavioral test was conducted at the ages of 6 and 12 months. The mice were sacrificed at 12-month age. One hemisphere of the brain was frozen-sectioned for immunohistochemistry and the other hemisphere was dissected into 7 regions. The levels of Aβ1-40, Aβ1-42 and 8-hydroxydeoxyguanosine (8-OHdG) in blood or/and brain samples were analyzed by ELISA. Secretase activities in brain regions were analyzed by in vitro assays. RESULTS The pre-mature death rate of transgenic mice was approximately 35% before 6-month age, and high levels of Aβ(1-40) and Aβ(1-42) were detected in these dead mice brains with a ratio of 1:10. The level of blood-borne Aβ at 6-month age was similar with that at 12-month age. Besides, Aβ(1-40) level in the blood was significantly higher than Aβ(1-42) level at the ages of 6 and 12 months (ratio 2.37:1). In contrast, the level of Aβ(1-42) in the brain (160.6 ng/mg protein) was higher than that of Aβ(1-40) (74 ng/mg protein) (ratio 2.17:1). In addition, the levels of Aβ(1-40) and Aβ(1-42) varied markedly among different brain regions. Aβ(1-42) level was significantly higher than Aβ(1-40) level in cerebellum, frontal and posterior cortex, and hippocampus. Secretase activity assays did not reveal major differences among different brain regions or between wild-type and transgenic mice, suggesting that the transgene PS1 did not lead to higher γ-secretase activity but was more efficient in producing Aβ(1-42) peptides. 8-OHdG, the biomarker of DNA oxidative damage, showed a trend of increase in the blood of transgenic mice, but with no significant difference, as compared with the wild-type mice. Behavioral tests showed that transgenic mice had significant memory deficits at 6-month age compared to wild-type controls, and the deficits were exacerbated at 12-month age with more errors. CONCLUSION These results suggest that this mouse model mimics the early-onset human AD and may represent full-blown disease at as early as 6-month age for experimental studies.
authors.affiliation: Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario.
authors.forename: Huaqi
authors.initials: H
authors.lastname: Xiong
authors.forename: Debbie
authors.initials: D
authors.lastname: Callaghan
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wodzinska
authors.forename: Jiejing
authors.initials: J
authors.lastname: Xu
authors.forename: Maryna
authors.initials: M
authors.lastname: Premyslova
authors.forename: Qing-Yan
authors.initials: QY
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Connelly
authors.forename: Wandong
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000523:psychology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D006801:Humans; D018782:Maze Learning; D008569:Memory Disorders / Q000150:complications / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D000080242:8-Hydroxy-2'-Deoxyguanosine; D053829:Amyloid Precursor Protein Secretases; D003849:Deoxyguanosine