Qualification and application of a liquid chromatography-tandem mass spectrometric method for the determination of human $A{\beta}1$-40 and $A{\beta}1$-42 peptides in transgenic mouse plasma using

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A liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed and applied for the determination of human $A{\beta}1$-40 and $A{\beta}1$-42 peptides in transgenic mouse plasma to support preclinical pharmacodynamics studies. The method consisted of micro-elution solid phase extraction for sample preparation and LC-MS/MS analysis in the negative ion mode using electrospray ionization for analysis. $^{15}N_{53}-A{\beta}1$-40 and $^{15}N_{55}-A{\beta}1$-42 peptides were used as internal standards. A quadratic regression (weighted 1/concentrations), with an equation $y=ax^2+bx+c$, was used to fit calibration curves over the concentration range of 0.500-100 ng/mL for both $A{\beta}1$-40 and $A{\beta}1$-42 peptides. For quality control samples at 6.00, 40.0 and 80.0 ng/mL from the qualification experiment, the within-run accuracy ranged from -2.69 to 0.583 % with precision values ${\geq}8.23%$ for $A{\beta}1$-40. Within-run accuracy ranged from -4.83 to 10.1 % with precision values ${\geq}8.87%$ for $A{\beta}1$-42. Samples from a pharmacodynamics study using Tg2576 transgenic mice were analyzed by this qualified LC-MS/MS method and concentrations were compared to those generated by ELISA. The two methods were shown to be comparable for $A{\beta}1$-40 quantification of samples from the Tg2576 amyloid precursor protein transgenic mouse model, but varied slightly for $A{\beta}1$-42.