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
George J. Yohrling, Kevin M. Felsenstein, Kelly A. Conway, Adriana Zupa-Fernandez, Doug E. Brenneman and H. Moore Arnold
Affiliation: Johnson and Johnson Pharmaceutical Research and Development, LLC, Drug Discovery-CNS Research, Welsh and McKean Roads, 41-2032, PO Box 776, Spring House,PA, USA 19477, USA.
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.
Keywords: Alzheimer's disease, amyloid beta, amyloid precursor protein, drug discovery, transgenic mice, immunoassay, gamma-secretase
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