Format

Send to

Choose Destination
Acta Neuropathol. 2016 Apr;131(4):525-37. doi: 10.1007/s00401-016-1546-0. Epub 2016 Feb 22.

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

Author information

1
Department of Neurology, University of Bonn, 53127, Bonn, Germany.
2
Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Germany.
3
Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.
4
LIFE & BRAIN Center, University of Bonn, 53127, Bonn, Germany.
5
German Center for Neurodegenerative Diseases (DZNE), 37077, Göttingen, Germany.
6
Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077, Göttingen, Germany.
7
Center for the Molecular Physiology of the Brain, University Medical Center, 37077, Göttingen, Germany.
8
German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
9
Laboratory of Neuropathology-Institute of Pathology, University of Ulm, 89081, Ulm, Germany.
10
Department of Neurology, University of Bonn, 53127, Bonn, Germany. Jochen.Walter@ukb.uni-bonn.de.

Abstract

Aggregation and toxicity of the amyloid β-peptide (Aβ) are considered as critical events in the initiation and progression of Alzheimer's disease (AD). Recent evidence indicated that soluble oligomeric Aβ assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the Aβ sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization of oligomers of the wild-type Aβ remain unclear. Here, we identified an Aβ variant phosphorylated at Ser26 residue (pSer26Aβ) in transgenic mouse models of AD and in human brain that shows contrasting spatio-temporal distribution as compared to non-phosphorylated Aβ (npAβ) or other modified Aβ species. pSer26Aβ is particularly abundant in intraneuronal deposits at very early stages of AD, but much less in extracellular plaques. pSer26Aβ 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, pSer26Aβ oligomers exert increased toxicity in human neurons as compared to other known Aβ species. Thus, pSer26Aβ could represent a critical species in the neurodegeneration during AD pathogenesis.

KEYWORDS:

Alzheimer’s disease; Amyloid oligomer; Granulovacuolar degeneration; Intraneuronal Abeta; Phosphorylation; Protein aggregation

PMID:
26898910
PMCID:
PMC4789232
DOI:
10.1007/s00401-016-1546-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center