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Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is characterized by β-amyloid plaques and intraneuronal τ aggregation usually associated with cerebral amyloid angiopathy (CAA). Both β-amyloid plaques and CAA deposits contain fibrillar aggregates of the amyloid β-peptide (Aβ). Aβ plaques and CAA develop first in neocortical areas of preclinical AD patients and, then, expand in a characteristic sequence into further brain regions with end-stage pathology in symptomatic AD patients. Aβ aggregates are not restricted to amyloid plaques and CAA. Soluble and several types of insoluble non-plaque- and non-CAA-associated Aβ aggregates have been described. Amyloid fibrils are products of a complex self-assembly process that involves different types of transient intermediates. Amongst these intermediate species are protofibrils and oligomers. Different variants of Aβ peptides may result from alternative processing or from mutations that lead to rare forms of familial AD. These variants can exhibit different self-assembly and aggregation properties. In addition, several post-translational modifications of Aβ have been described that result, for example, in the production of N-terminal truncated Aβ with pyroglutamate modification at position 3 (AβN3pE) or of Aβ phosphorylated at serine 8 (pSer8Aβ). Both AβN3pE and pSer8Aβ show enhanced aggregation into oligomers and fibrils. However, the earliest detectable soluble and insoluble Aβ aggregates in the human brain exhibit non-modified Aβ, whereas AβN3pE and pSer8Aβ are detected in later stages. This finding indicates the existence of different biochemical stages of Aβ aggregate maturation with pSer8Aβ being related mainly to cases with symptomatic AD. The conversion from preclinical to symptomatic AD could thereby be related to combined effects of increased Aβ concentration, maturation of aggregates and spread of deposits into additional brain regions. Thus, the inhibition of Aβ aggregation and maturation before entering the symptomatic stage of the disease as indicated by the accumulation of pSer8Aβ may represent an attractive treatment strategy for preventing disease progression.

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Acknowledgments

The authors thank Bill Close (Institute for Pharmaceutical Biotechnology, Center for Biomedical Research, University of Ulm, Germany) for reading the manuscript. This study was supported by DFG-Grants TH624/6-1 (DRT), WA1477/6 (JW), FA456/12-1 (MF) and Alzheimer Forschung Initiative Grants #10810, 13803 (DRT).

Conflict of interest

DRT received consultancies from Covance Laboratories (UK) and GE-Healthcare (UK), received a speaker honorarium from GE-Healthcare (UK) and collaborated with Novartis Pharma Basel (Switzerland).

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Authors and Affiliations

  1. Laboratory of Neuropathology, Institute of Pathology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, Ulm, Germany

    Dietmar Rudolf Thal

  2. Department of Neurology, University of Bonn, Sigmund Freud Strasse 25, 53127, Bonn, Germany

    Jochen Walter

  3. Laboratory of Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, 351-0198, Japan

    Takaomi C. Saido

  4. Institute for Pharmaceutical Biotechnology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, 89081, Ulm, Germany

    Marcus Fändrich

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  1. Dietmar Rudolf Thal
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Thal, D.R., Walter, J., Saido, T.C. et al. Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease. Acta Neuropathol 129, 167–182 (2015). https://doi.org/10.1007/s00401-014-1375-y

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