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 (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.
Portelius
Erik
E
Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden. erik.portelius@neuro.gu.se
Bogdanovic
Nenad
N
Gustavsson
Mikael K
MK
Volkmann
Inga
I
Brinkmalm
Gunnar
G
Zetterberg
Henrik
H
Winblad
Bengt
B
Blennow
Kaj
K
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000145:classification* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D013223:Statistics as Topic
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D020033:Protein Isoforms; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)