Gandy et al. compare our results with their 1994 findings that the amino-terminally truncated amyloid Aβ11-42 was relatively abundant in two cases of familial Alzheimer′s disease involving two distinct mutations in -APP. However, four important differences should be borne in mind: The authors compare Aβ11-42 with Aβ1-42 and ignore Aβ1-40, although both Aβ1-40 and Aβ1-42 are generated by β-secretase/BACE cleavage at residue Asp 1 (ref. 3); their data are not correlated with features related to disease severity, such as age at onset and duration; they did not examine brains with PS1 mutations (these were not known at that time); and their characterization was based on the use of size-exclusion chromatography and electrospray mass spectrometry to quantify formic-acid-extracted Aβ, whereas we used quantitative analysis of immunoprecipitated water-soluble Aβ on western blots, mass spectrometry to identify Aβ variants, and immunohistochemistry to reveal amino-truncated A peptides in plaques.
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