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

Publisher： Bentham Science Publishers

E-ISSN： 1875-5828|4|3|297-303

ISSN： 1567-2050

Source： Current Alzheimer Research, Vol.4, Iss.3, 2007-07, pp. : 297-303

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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 (A&bgr;) 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 A&bgr;. 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 A&bgr; levels were validated and quantified with a rodent-specific monoclonal A&bgr; antibody. Plasma A&bgr; 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 A&bgr; 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 A&bgr; levels that were significantly greater than A&bgr; levels in B6D2F1 mice (242 ± 20 pM). In vivo efficacy of an A&bgr; lowering agent was observed in CF-1 mice upon oral administration of the &ggr;-secretase inhibitors, DAPT and LY-411575. The absolute levels of rodent brain A&bgr; detected and the efficacy of the &ggr;-secretase treatment were dependent upon the antibodies used, as well as the extraction methodology. The measurement of total brain A&bgr; 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.