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.
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.
Yohrling
George J
GJ
CNS Research, Johnson and Johnson Pharmaceutical Research and Development, LLC, Spring House, PA 19477, USA. gyohrlin@prdus.jnj.com
Felsenstein
Kevin M
KM
Conway
Kelly A
KA
Zupa-Fernandez
Adriana
A
Brenneman
Doug E
DE
Arnold
H Moore
HM
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
D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases