In vivo effects of APP are not exacerbated by BACE2 co-overexpression: behavioural characterization of a double transgenic mouse model
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Down syndrome, the most common genetic disorder leading to mental retardation, is caused by the presence of all or part of an extra copy of chromosome 21. At relatively early ages, Down syndrome patients develop progressive formation and extracellular aggregation of amyloid-β peptide, considered as one of the causal factors for the pathogenesis of Alzheimer’s disease. This neuropathological hallmark has been attributed to the overexpression of APP but could also be contributed by other HSA21 genes. BACE2 maps to HSA21 and is homologous to BACE1, a β-secretase involved in the amyloidogenic pathway of APP proteolysis, and thus it has been hypothesized that the co-overexpression of both genes could contribute to Alzheimer’s like neuropathology present in Down syndrome. The aim of the present study has been to analyse the impact of the co-overexpression of BACE2 and APP, using a double transgenic mouse model. Double transgenic mice did not present any neurological or sensorimotor alterations, nor genotype-dependent anxiety-like behaviour or age-associated cognitive dysfunction. Interestingly, TgBACE2-APP mice showed deregulation of BACE2 expression levels that were significantly increased with respect to single TgBACE2 mice. Co-overexpression of BACE2 and APP did not increase amyloid-β peptide concentration in brain. Our results suggest that the in vivo effects of APP are not exacerbated by BACE2 co-overexpression but may have some protective effects in specific behavioural and cognitive domains in transgenic mice.
KeywordsDown syndrome Alzheimer disease BACE2 APP Chromosome 21
We thank Jerome McDonald and Nuno Duarte Sendas Sampaio de Vasconcelos for their technical support. The laboratory of M.D. is supported by the DURSI (2009SGR1313) and the Departament de Salut of the Catalan Autonomous Government. This work was supported by grants from the Spanish Ministry of Education and Science (FCT-08-0782, SAF2007-60827, SAF2007-31093-E), FIS (PI 082038), Marató TV3 (062230), Jerome Lejeune Foundation (JMLM/AC/08-044), Reina Sofia and Areces Foundations and EU (LSHG-CT-2006-037627; EU/FIS PS09102673, CureFXS ERA-NET E-Rare: EU/FIS PS09102673). The CIBER of Enfermedades Raras is an initiative of the ISCIII. G.A. received additional support from the Basque Government (BFI05.48).
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