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

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Abstract

A proposed key event in the pathogenesis of Alzheimer’s disease (AD) is the formation of neurotoxic amyloid β (Aβ) 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 Αβ (Aβ1-42), which is thought to initiate plaque formation and AD pathogenesis. Numerous isoforms of Aβ, e.g., Aβ1-42, Aβ1-40 and the 3-pyroglutamate derivate of Aβ3-42 (pGluAβ3-42), 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 Aβ 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 Aβ isoforms in the three different brain regions analyzed from control, SAD, and FAD are Aβ1-42, pGluAβ3-42, Aβ4-42 and Aβ1-40 of which Aβ1-42 and Aβ4-42 are the dominant isoforms in the hippocampus and the cortex in all groups analyzed, controls included. No prominent differences in Aβ isoform patterns between FAD and SAD patients were seen, underscoring the similarity in the amyloid pathology of these two disease entities.

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Acknowledgments

This work was supported by grants from the Swedish Research Council (projects 2006-6227, 2006-2740 and 2006-3505), the Alzheimer’s Association (NIRG-08-90356), cNEUPRO, the Royal Swedish Academy of Sciences, the Sahlgrenska University Hospital, the Inga-Britt and Arne Lundberg Research Foundation, the Göteborg Medical Society, the Swedish Medical Society, Swedish Brain Power, Stiftelsen Gamla Tjänarinnor, Gun och Bertil Stohnes stiftelse, Åhlén-stiftelsen, Alzheimer Foundation, Sweden, U.S. PHS K08 AG-22228, AG-O5131 and AG-023185.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 431 80, Mölndal, Sweden

    Erik Portelius, Mikael K. Gustavsson, Gunnar Brinkmalm, Henrik Zetterberg & Kaj Blennow

  2. Alzheimer Disease Research Center, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden

    Nenad Bogdanovic, Inga Volkmann & Bengt Winblad

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  1. Erik Portelius
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  2. Nenad Bogdanovic
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Correspondence to Erik Portelius.

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Portelius, E., Bogdanovic, N., Gustavsson, M.K. et al. Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer’s disease. Acta Neuropathol 120, 185–193 (2010). https://doi.org/10.1007/s00401-010-0690-1

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  • DOI: https://doi.org/10.1007/s00401-010-0690-1

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