Schematic representation of Aβ processing and aggregation. (A) Primary sequence of human Aß1-42 with examples of natural or designed intra-Aß mutations (above sequence) and post-translational modifications (below sequence). (B) Amyloid precursor protein (APP) cleavage by β- and γ- secretases releases aggregation-prone Aβ peptides, particularly Aβ1-42. Intra-Aβ mutations and post-translational modifications increase Aβ ability to aggregate even more. It has been suggested that diffusible Aβ aggregates rather than monomer form or fibrils are the synaptotoxic species. These aggregates include ADDLS (Aß-derived diffusible ligands), globulomers (globule-like 12-mers), Aß*56 (56 kDa Aß-containing aggregates derived from brain), protofibrils (soluble, short fibril-shaped often “worm-like” structures) and annular protofibrils (protofibrils that can form pores in membranes). Other aggregation-prone proteins also form synaptotoxic soluble species that may share conformation recognized by antibodies.