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Current Alzheimer Research
ISSN (Print): 1567-2050
ISSN (Online): 1875-5828
VOLUME: 4
ISSUE: 3
DOI: 10.2174/156720507781077269      Price:  $58









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

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Author(s): George J. Yohrling, Kevin M. Felsenstein, Kelly A. Conway, Adriana Zupa-Fernandez, Doug E. Brenneman and H. Moore Arnold
Pages 297-303 (7)
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.
Keywords:
Alzheimer's disease, amyloid beta, amyloid precursor protein, drug discovery, transgenic mice, immunoassay, gamma-secretase
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.