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Journal Article

Phosphorylation of the amyloid beta-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity.

MPS-Authors
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Rezaei-Ghaleh,  N.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

Fulltext (public)

2262617.pdf
(Publisher version), 10MB

Supplementary Material (public)

2262617_Suppl.pdf
(Supplementary material), 2MB

Citation

Kumar, S., Wirths, O., Stüber, K., Wunderlich, P., Koch, P., Theil, S., et al. (2016). Phosphorylation of the amyloid beta-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity. Acta Neuropathologica, 131(4), 525-537. doi:10.1007/s00401-016-1546-0.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002A-21E6-2
Abstract
Aggregation and toxicity of the amyloid beta-peptide (A beta) are considered as critical events in the initiation and progression of Alzheimer's disease (AD). Recent evidence indicated that soluble oligomeric A beta assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the A beta sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization of oligomers of the wild-type A beta remain unclear. Here, we identified an A beta variant phosphorylated at Ser26 residue (pSer26A beta) in transgenic mouse models of AD and in human brain that shows contrasting spatio-temporal distribution as compared to non-phosphorylated A beta (npA beta) or other modified A beta species. pSer26A beta is particularly abundant in intraneuronal deposits at very early stages of AD, but much less in extracellular plaques. pSer26A beta assembles into a specific oligomeric form that does not proceed further into larger fibrillar aggregates, and accumulates in characteristic intracellular compartments of granulovacuolar degeneration together with TDP-43 and phosphorylated tau. Importantly, pSer26A beta oligomers exert increased toxicity in human neurons as compared to other known A beta species. Thus, pSer26A beta could represent a critical species in the neurodegeneration during AD pathogenesis.