Neuropathology and biochemistry of A[beta] and its aggregates in Alzheimer's disease

• Published in: Acta neuropathologica 2015-02, Vol.129 (2), p.167
• Main Authors: Thai, Dietmar Rudolf, Walter, Jochen, Saido, Takaomi C, Fandrich, Marcus
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Biochemistry; Brain; Development and progression; Oligomers; Peptides
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-014-1375-y

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 (A[beta]). A[beta] 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. A[beta] aggregates are not restricted to amyloid plaques and CAA. Soluble and several types of insoluble non-plaque- and non-CAA-associated A[beta] 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 A[beta] 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 A[beta] have been described that result, for example, in the production of N-terminal truncated A[beta] with pyroglutamate modification at position 3 ([A[beta].sub.N3pE]) or of A[beta] phosphorylated at serine 8 (pSer8AP). Both [A[beta].sub.N3pE] and pSer8A[beta] show enhanced aggregation into oligomers and fibrils. However, the earliest detectable soluble and insoluble A[beta] aggregates in the human brain exhibit non-modified A[beta], whereas [A[beta].sub.N3pE] and pSer8A[beta] are detected in later stages. This finding indicates the existence of different biochemical stages of A[beta] aggregate maturation with pSer8A[beta] being related mainly to cases with symptomatic AD. The conversion from preclinical to symptomatic AD could thereby be related to combined effects of increased A[beta] concentration, maturation of aggregates and spread of deposits into additional brain regions. Thus, the inhibition of A[beta] aggregation and maturation before entering the symptomatic stage of the disease as indicated by the accumulation of pSer8AP may represent an attractive treatment strategy for preventing disease progression. Keywords Amyloid * Oligomers * Fibrils * Plaques * Alzheimer * Peptide modification * Preclinical AD