Abstract
In this study, we report a detailed analysis of the different variants of amyloid-β (Aβ) peptides in the brains and the cerebrospinal fluid from APP23 transgenic mice, expressing amyloid precursor protein with the Swedish familial Alzheimer disease mutation, at different ages. Using one- and two-dimensional gel electrophoresis, immunoblotting, and mass spectrometry, we identified the Aβ peptides Aβ(1-40), -(1-42), -(1-39), -(1-38), -(1-37), -(2-40), and -(3-40) as well as minor amounts of pyroglutamate-modified Aβ (Aβ(N3pE)) and endogenous murine Aβ in brains from 24-month-old mice. Chemical modifications of the N-terminal amino group of Aβ were identified that had clearly been introduced during standard experimental procedures. To address this issue, we additionally applied amyloid extraction in ultrapure water. Clear differences between APP23 mice and Alzheimer disease (AD) brain samples were observed in terms of the relative abundance of specific variants of Aβ peptides, such as Aβ(N3pE), Aβ(1-42), and N-terminally truncated Aβ(2/3-42). These differences to human AD amyloid were also noticed in a related mouse line transgenic for human wild type amyloid precursor protein. Taken together, our findings suggest different underlying molecular mechanisms driving the amyloid deposition in transgenic mice and AD patients.
Highlights
We report a detailed analysis of the different variants of amyloid- (A) peptides in the brains and the cerebrospinal fluid from APP23 transgenic mice, expressing amyloid precursor protein with the Swedish familial Alzheimer disease mutation, at different ages
We present here a detailed immunoblot and mass spectrometry analysis of the different variants of A peptides that can be detected after one- and two-dimensional electrophoretic separation in brain extracts and cerebrospinal fluid (CSF) from heterozygous APP23 mice at different ages
To provide further information regarding the relative abundance of N-truncated A peptides in the APP23 mice as compared with an example of human Alzheimer disease (AD) amyloid pathology, we applied two-dimensional separation followed by immunoblotting with mAb 6E10
Summary
76 Female ⑀4/⑀2 88 Female ⑀4/⑀3 79 Male ⑀3/⑀3 Female ⑀4/⑀3 Male ⑀4/⑀3 a For this individual, a Braak stage for amyloid was not explicitly indicated. According to the information provided, “classical senile plaques were rather frequent.”. Expression and processing of a familial Alzheimer disease mutant APP form, we investigated brain extracts and CSF from APP51 mice that are transgenic for human wild type APP751 (22)
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