title: A comparative analysis of brain and plasma Abeta levels in eight common non-transgenic mouse strains: validation of a specific immunoassay for total rodent Abeta.
abstract: Transgenic mouse models of Alzheimer's disease (AD) are being utilized as models for elucidating AD etiology and potential therapeutic approaches. However, two major drawbacks of these models are: (1) transgenic animals often over-express amyloid beta (Abeta) to high levels compared to that seen in sporadic human AD and (2) the current intellectual property issues surrounding a number of these models make them difficult to utilize in a commercial setting. Our goal was to identify an appropriate non-transgenic mouse strain, devoid of these patent restrictions and test whether amyloid-modulating compounds will lower total brain and plasma Abeta. Plasma and brain samples were collected from eight commonly used mouse strains (C57BL/6, SJL, CF-1, DBA/2, CD-1, 129, FVB and B6D2F1; Charles River Labs) and total Abetalevels were validated and quantified with a rodent-specific monoclonal Abetaantibody. Plasma Abeta in SJL mice was the highest of the eight strains tested (213 pM +/- 21 pM), but was not significantly different than the seven other strains. Total brain Abeta in SJL mice was also the greatest of the mouse strains tested (356 pM +/- 73 pM). SJL, C57BL/6 and CF-1 mice had total brain Abeta levels that were significantly greater than Abeta levels in B6D2F1 mice (242 +/- 20 pM). In vivo efficacy of an Abeta lowering agent was observed in CF-1 mice upon oral administration of the gamma-secretase inhibitors, DAPT and LY-411575. The absolute levels of rodent brain Abeta detected and the efficacy of the gamma-secretase treatment were dependent upon the antibodies used, as well as the extraction methodology. The measurement of total brain Abeta lowering in a common mouse strain could help accelerate drug discovery programs for Alzheimer's disease without relying on costly transgenic animals that overexpress APP in a manner that may not be predictive of the effects of these compounds in human AD.
authors.affiliation: CNS Research, Johnson and Johnson Pharmaceutical Research and Development, LLC, Spring House, PA 19477, USA. gyohrlin@prdus.jnj.com
authors.forename: George J
authors.initials: GJ
authors.lastname: Yohrling
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Felsenstein
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Conway
authors.forename: Adriana
authors.initials: A
authors.lastname: Zupa-Fernandez
authors.forename: Doug E
authors.initials: DE
authors.lastname: Brenneman
authors.forename: H Moore
authors.initials: HM
authors.lastname: Arnold
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000097:blood*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008297:Male; D051379:Mice; D015203:Reproducibility of Results; D013045:Species Specificity
chemical_list: D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases