A Comparative Analysis of Brain and Plasma Aβ Levels in Eight Common Non-Transgenic Mouse Strains: Validation of a Specific Immunoassay for Total Rodent Aβ

Title: A Comparative Analysis of Brain and Plasma Aβ Levels in Eight Common Non-Transgenic Mouse Strains: Validation of a Specific Immunoassay for Total Rodent Aβ

Volume: 4 Issue: 3

Author(s): George J. Yohrling, Kevin M. Felsenstein, Kelly A. Conway, Adriana Zupa-Fernandez, Doug E. Brenneman and H. Moore Arnold

Affiliation:

Keywords: Alzheimer's disease, amyloid beta, amyloid precursor protein, drug discovery, transgenic mice, immunoassay, gamma-secretase

Abstract: Transgenic mouse models of Alzheimers 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 (Aβ) 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 Aβ. 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 Aβ levels were validated and quantified with a rodent-specific monoclonal Aβ antibody. Plasma Aβ 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 Aβ 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 Aβ levels that were significantly greater than Aβ levels in B6D2F1 mice (242 ± 20 pM). In vivo efficacy of an Aβ lowering agent was observed in CF-1 mice upon oral administration of the γ-secretase inhibitors, DAPT and LY-411575. The absolute levels of rodent brain Aβ detected and the efficacy of the γ-secretase treatment were dependent upon the antibodies used, as well as the extraction methodology. The measurement of total brain Aβ lowering in a common mouse strain could help accelerate drug discovery programs for Alzheimers 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.

Cite this article as:

George J. Yohrling , Kevin M. Felsenstein , Kelly A. Conway , Adriana Zupa-Fernandez , Doug E. Brenneman and H. Moore Arnold , A Comparative Analysis of Brain and Plasma Aβ Levels in Eight Common Non-Transgenic Mouse Strains: Validation of a Specific Immunoassay for Total Rodent Aβ, Current Alzheimer Research 2007; 4 (3) . https://dx.doi.org/10.2174/156720507781077269