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Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer’s disease

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Abstract

The progressive accumulation of extracellular amyloid plaques in the brain is a common hallmark of Alzheimer’s disease (AD). We recently identified a novel species of Aβ phosphorylated at serine residue 8 with increased propensity to form toxic aggregates as compared to non-phosphorylated species. The age-dependent analysis of Aβ depositions using novel monoclonal phosphorylation-state specific antibodies revealed that phosphorylated Aβ variants accumulate first inside of neurons in a mouse model of AD already at 2 month of age. At higher ages, phosphorylated Aβ is also abundantly detected in extracellular plaques. Besides a large overlap in the spatiotemporal deposition of phosphorylated and non-phosphorylated Aβ species, fractionized extraction of Aβ from brains revealed an increased accumulation of phosphorylated Aβ in oligomeric assemblies as compared to non-phosphorylated Aβ in vivo. Thus, phosphorylated Aβ could represent an important species in the formation and stabilization of neurotoxic aggregates, and might be targeted for AD therapy and diagnosis.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-β-peptide

NFT:

Neurofibrillary tangles

APP:

Amyloid precursor protein

CTFs:

C-terminal fragments

npAβ:

Non-phosphorylated Aβ

pAβ:

Phosphorylated Aβ

ELISA:

Enzyme-linked immunosorbent assay

WB:

Western blotting

IHC:

Immunohistochemistry

BSA:

Bovine serum albumin

PBS:

Phosphate buffered saline

SDS:

Sodium dodecyl sulphate

PAGE:

Polyacrylamide gel electrophoresis

Fl-APP:

Full-length APP

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Acknowledgments

We thank Dr. G. Multhaup for providing rabbit polyclonal 692 antibodies specific against human Aß. We also thank Drs. M.T. Heneka and M.P. Kummer for providing nitrated Aß. This study was supported by the Deutsche Forschungsgemeinschaft (DFG) to J.W. (WA1477/6, SFB645, and KFo177) and to S.K. by the Alzheimer Forschung Initiative e.V. (AFI # 12854).

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Authors and Affiliations

  1. Department of Neurology, University of Bonn, 53127, Bonn, Germany

    Sathish Kumar, Sandra Theil, Janina Gerth & Jochen Walter

  2. Department of Psychiatry, Division of Molecular Psychiatry, Georg-August-University Göttingen, University Medicine Göttingen, von-Siebold-Str. 5, 37075, Göttingen, Germany

    Oliver Wirths & Thomas A. Bayer

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Correspondence to Jochen Walter.

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Kumar, S., Wirths, O., Theil, S. et al. Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer’s disease. Acta Neuropathol 125, 699–709 (2013). https://doi.org/10.1007/s00401-013-1107-8

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