Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer's disease.

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Thal DR, Walter J, Saido TC, Fandrich M

Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer's disease.

Acta Neuropathol. 2015 Feb;129(2):167-82. doi: 10.1007/s00401-014-1375-y. Epub 2014 Dec 23.

PubMed ID
25534025 [ View in PubMed
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Abstract

Alzheimer's disease (AD) is characterized by beta-amyloid plaques and intraneuronal tau aggregation usually associated with cerebral amyloid angiopathy (CAA). Both beta-amyloid plaques and CAA deposits contain fibrillar aggregates of the amyloid beta-peptide (Abeta). Abeta 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. Abeta aggregates are not restricted to amyloid plaques and CAA. Soluble and several types of insoluble non-plaque- and non-CAA-associated Abeta 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 Abeta 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 Abeta have been described that result, for example, in the production of N-terminal truncated Abeta with pyroglutamate modification at position 3 (AbetaN3pE) or of Abeta phosphorylated at serine 8 (pSer8Abeta). Both AbetaN3pE and pSer8Abeta show enhanced aggregation into oligomers and fibrils. However, the earliest detectable soluble and insoluble Abeta aggregates in the human brain exhibit non-modified Abeta, whereas AbetaN3pE and pSer8Abeta are detected in later stages. This finding indicates the existence of different biochemical stages of Abeta aggregate maturation with pSer8Abeta being related mainly to cases with symptomatic AD. The conversion from preclinical to symptomatic AD could thereby be related to combined effects of increased Abeta concentration, maturation of aggregates and spread of deposits into additional brain regions. Thus, the inhibition of Abeta aggregation and maturation before entering the symptomatic stage of the disease as indicated by the accumulation of pSer8Abeta may represent an attractive treatment strategy for preventing disease progression.

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