A proposed key event in the pathogenesis of
Alzheimer's disease (AD) is the formation of neurotoxic
amyloid beta (Abeta) 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 Alphabeta (Abeta1-42), which is thought to initiate plaque formation and AD pathogenesis. Numerous
isoforms of Abeta, e.g., Abeta1-42, Abeta1-40 and the 3-pyroglutamate derivate of Abeta3-42 (pGluAbeta3-42), 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 Abeta
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 Abeta
isoforms in the three different brain regions analyzed from control, SAD, and
FAD are Abeta1-42, pGluAbeta3-42, Abeta4-42 and Abeta1-40 of which Abeta1-42 and Abeta4-42 are the dominant
isoforms in the hippocampus and the cortex in all groups analyzed, controls included. No prominent differences in Abeta
isoform patterns between
FAD and SAD patients were seen, underscoring the similarity in the
amyloid pathology of these two disease entities.