Figure 1

Pathways of aggregation and observed Aß-aggregate intermediates. Monomeric Aß folds to the activated state and then exists in rapid equilibrium with low molecular weight oligomers, which aggregate over various transient high molecular weight intermediates to matured fibrils. The definition of LMW and HMW oligomers is related to the elution profile of Aß-aggregates in size exclusion chromatography, revealing two predominant peaks at the exclusion limit (>60 kDa) and at the void volume (4-20 kDa), respectively. The HMW intermediates comprise pentamers, hexamers and multiples thereof, finally forming protofibrils, which are the precursors for multi-stranded ribbons of matured fibrils. Further neurotoxic aggregate species e.g. AßO, ADDL and ASPD are believed to aggregate over alternative pathways but preliminary data revealed that these are able to converge into the other pathways of aggregation (inter-conversion). Interestingly, every change in the experimental paradigm can provoke this aggregate conversion. Therefore, one might assume that many different aggregates coexist and, thus, neurotoxicity can be attributed to several pathogenic modes of action. Monomers and fibrils are believed to be biologically inert; however fibrils are able to collapse into protofibrils and then also reveal toxicity. The broad range of prefibrillar aggregates have been reported as pathophysiologically relevant in AD.