title: Phosphorylation of the amyloid β-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity.
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.
authors.affiliation: Department of Neurology, University of Bonn, 53127, Bonn, Germany.
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.|LIFE & BRAIN Center, University of Bonn, 53127, Bonn, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Stüber
authors.affiliation: Department of Neurology, University of Bonn, 53127, Bonn, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wunderlich
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.|LIFE & BRAIN Center, University of Bonn, 53127, Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Koch
authors.affiliation: Department of Neurology, University of Bonn, 53127, Bonn, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Theil
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 37077, Göttingen, Germany.
authors.forename: Nasrollah
authors.initials: N
authors.lastname: Rezaei-Ghaleh
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 37077, Göttingen, Germany.|Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077, Göttingen, Germany.|Center for the Molecular Physiology of the Brain, University Medical Center, 37077, Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.|LIFE & BRAIN Center, University of Bonn, 53127, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Brüstle
authors.affiliation: Laboratory of Neuropathology-Institute of Pathology, University of Ulm, 89081, Ulm, Germany.
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.affiliation: Department of Neurology, University of Bonn, 53127, Bonn, Germany. Jochen.Walter@ukb.uni-bonn.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells; D009447:Neuroblastoma / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D066329:Protein Aggregates / Q000235:genetics; D012694:Serine / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D066329:Protein Aggregates; D012694:Serine
keywords: Alzheimer’s disease; Amyloid oligomer; Granulovacuolar degeneration; Intraneuronal Abeta; Phosphorylation; Protein aggregation