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

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(N3pE)) or of A beta phosphorylated at serine 8 (pSer8A beta). Both A beta(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(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 pSer8A beta may represent an attractive treatment strategy for preventing disease progression.