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


ABSTRACT: Aggregation and toxicity of the amyloid ?-peptide (A?) are considered as critical events in the initiation and progression of Alzheimer's disease (AD). Recent evidence indicated that soluble oligomeric A? assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the A? sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization of oligomers of the wild-type A? remain unclear. Here, we identified an A? variant phosphorylated at Ser26 residue (pSer26A?) in transgenic mouse models of AD and in human brain that shows contrasting spatio-temporal distribution as compared to non-phosphorylated A? (npA?) or other modified A? species. pSer26A? is particularly abundant in intraneuronal deposits at very early stages of AD, but much less in extracellular plaques. pSer26A? 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? oligomers exert increased toxicity in human neurons as compared to other known A? species. Thus, pSer26A? could represent a critical species in the neurodegeneration during AD pathogenesis.

SUBMITTER: Kumar S 

PROVIDER: S-EPMC4789232 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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