Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer's disease

A proposed key event in the pathogenesis of Alzheimer's disease (AD) is the formation of neurotoxic amyloid beta (A beta) oligomers and amyloid plaques in specific brain regions that are affected by the disease. The main plaque component is the 42 amino acid isoform of II(2) (A beta 1-42), which is thought to initiate plaque formation and AD pathogenesis. Numerous isoforms of A beta, e.g., A beta 1-42, A beta 1-40 and the 3-pyroglutamate derivate of A beta 3-42 (pGluA beta 3-42), have been detected in the brains of sporadic AD (SAD) and familial AD (FAD) subjects. However, the relative importance of these isoforms in the pathogenesis of AD is not fully understood. Here, we report a detailed study using immunoprecipitation in combination with mass spectrometric analysis to determine the A beta isoform pattern in the cerebellum, cortex and hippocampus in AD, including subjects with a mutation in the presenilin (M146V) or amyloid precursor protein (KM670/671NL) genes, SAD subjects and non-demented controls. We show that the dominating A beta isoforms in the three different brain regions analyzed from control, SAD, and FAD are A beta 1-42, pGluA beta 3-42, A beta 4-42 and A beta 1-40 of which A beta 1-42 and A beta 4-42 are the dominant isoforms in the hippocampus and the cortex in all groups analyzed, controls included. No prominent differences in A beta isoform patterns between FAD and SAD patients were seen, underscoring the similarity in the amyloid pathology of these two disease entities.