title: In vivo effects of APP are not exacerbated by BACE2 co-overexpression: behavioural characterization of a double transgenic mouse model.
abstract: 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.
authors.affiliation: Neurobehavioural Phenotyping of Mouse Models of Disease, Genes and Disease Program, Center for Genomic Regulation (CRG), Barcelona Biomedical Research Park (PRBB), Dr. Aiguader, 88, 08003, Barcelona, Catalonia, Spain.
authors.forename: Garikoitz
authors.initials: G
authors.lastname: Azkona
authors.forename: Ditsa
authors.initials: D
authors.lastname: Levannon
authors.forename: Yoram
authors.initials: Y
authors.lastname: Groner
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D016564:Amyloid beta-Protein Precursor; C509285:Bace2 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases