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

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-21E6-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-DDB5-B
Genre: Journal Article

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 Creators:
Kumar, S., Author
Wirths, O., Author
Stüber, K., Author
Wunderlich, P., Author
Koch, P., Author
Theil, S., Author
Rezaei-Ghaleh, N.1, Author              
Zweckstetter, M.1, Author              
Bayer, T. A., Author
Bruestle, O., Author
Thal, D. R., Author
Walter, J., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: Alzheimer's disease; Phosphorylation; Protein aggregation; Intraneuronal Abeta; Amyloid oligomer; Granulovacuolar degeneration
 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.

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Language(s): eng - English
 Dates: 2016-02-222016-04
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1007/s00401-016-1546-0
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Title: Acta Neuropathologica
Source Genre: Journal
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Pages: - Volume / Issue: 131 (4) Sequence Number: - Start / End Page: 525 - 537 Identifier: -