The culprit behind amyloid beta peptide related neurotoxicity in Alzheimer's disease: oligomer size or conformation?

The original amyloid cascade hypothesis for Alzheimer's disease (AD) [1] has recently been reformulated to focus on soluble aggregates as the pathogenic molecular form of the amyloid beta peptide (Aβ) [2] (Figure 1). Aβ is naturally presentin the brain and cerebrospinal fluid of humans throughout life [3]. Its role is currently unknown. The mere presence of Aβ in the brain is not sufficient to cause symptoms of neurodegeneration. It has been recognized previously that neuronal injury is rather the result of ordered Aβ self-association [4]. The amyloid plaques found in AD patient brains, which serve as a hallmark for AD, have been found to contain vast amounts of Aβ organized into amyloid fibrils. There is no clear correlation, however, between the presence of the Aβ containing plaques in the brain and the severity of the neurodegenerative symptoms observed in AD patients [5]. Therefore, the focus of research in this area has shifted from senile plaques toward soluble oligomeric conformations of Aβ as the toxic species as these strongly correlate with the severity of dementia [2,6,7]. This oligomeric form of Aβ is highly toxic to the brain and is the trigger for loss of synapses and neuronal damage [8,9]. Because of this, many laboratories have been hunting for a specific molecular assembly of defined size that is the main trigger of AD. The result has been the identification of a host of molecular species of Aβ, ranging from dimers [10-12], trimers [13] and Aβ species with a molecular weight of 56 kDa [14] to Aβ-derived diffusible ligands (ADDLs) [15,16] and protofibrils [17] in potent neurotoxic fractions. All are capable of impairing memory formation in mice and their formation and significant accumulation in the brain should thus be considered a potential cause of AD.Recent in vitro studies of the amyloid formation of Aβ demonstrate that the species mentioned all occur but that they are only transiently populated [18-21]. Moreover, their isolation and characteriz