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01-02-2015 | Review

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

Authors: Dietmar Rudolf Thal, Jochen Walter, Takaomi C. Saido, Marcus Fändrich

Published in: Acta Neuropathologica | Issue 2/2015

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 (Aβ_N3pE) or of Aβ phosphorylated at serine 8 (pSer8Aβ). Both Aβ_N3pE 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 Aβ_N3pE 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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Title: Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease
Authors: Dietmar Rudolf Thal
Jochen Walter
Takaomi C. Saido
Marcus Fändrich
Publication date: 01-02-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 2/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-014-1375-y

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

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