Experimental findings suggest that oligomeric forms of the amyloid β protein (Aβ) play a critical role in Alzheimer's disease. Thus, elucidating their structure and the mechanisms of their formation is critical for developing therapeutic agents. We use discrete molecular dynamics simulations and a four-bead protein model to study oligomerization of two predominant alloforms, Aβ40 and Aβ42, at the atomic level. The four-bead model incorporates backbone hydrogen-bond interactions and amino acid-specific interactions mediated through hydrophobic and hydrophilic elements of the side chains. During the simulations we observe monomer folding and aggregation of monomers into oligomers of variable sizes. Aβ40 forms significantly more dimers than Aβ42, whereas pentamers are significantly more abundant in Aβ42 relative to Aβ40. Structure analysis reveals a turn centered at Gly-37–Gly-38 that is present in a folded Aβ42 monomer but not in a folded Aβ40 monomer and is associated with the first contacts that form during monomer folding. Our results suggest that this turn plays an important role in Aβ42 pentamer formation. Aβ pentamers have a globular structure comprising hydrophobic residues within the pentamer's core and hydrophilic N-terminal residues at the surface of the pentamer. The N termini of Aβ40 pentamers are more spatially restricted than Aβ42 pentamers. Aβ40 pentamers form a β-strand structure involving Ala-2–Phe-4, which is absent in Aβ42 pentamers. These structural differences imply a different degree of hydrophobic core exposure between pentamers of the two alloforms, with the hydrophobic core of the Aβ42 pentamer being more exposed and thus more prone to form larger oligomers.

The brains of Alzheimer’s disease patients contain extracellular Aβ amyloid deposits (senile plaques). Although genetic evidence causally links Aβ deposition to the disease, the mechanism by which Aβ disrupts cortical function is unknown. Using triple immunofluorescent confocal microscopy and three-dimensional reconstructions, we found that neuronal processes that cross through an Aβ deposit are likely to have a radically changed morphology. We modeled the electrophysiological effect of this changed morphology and found a predicted delay of several milliseconds over an average plaque. We propose that this type of delay, played out among thousands of plaques throughout neocortical areas, disrupts the precise temporal firing patterns of action potentials, contributing directly to neural system failure and dementia.

Despite extensive deposition of putatively neurotoxic amyloid-β (Aβ) protein in the brain, it has not been possible to demonstrate an association of Aβ deposits with neuronal loss in Alzheimer's disease (AD), and neuronal loss is minimal in transgenic mouse models of AD. Using triple immunostaining confocal microscopy and analyzing the images with the cross-correlation density map method from statistical physics, we directly compared Aβ deposition, Aβ morphology, and neuronal architecture. We found dramatic, focal neuronal toxicity associated primarily with thioflavin S-positive fibrillar Aβ deposits in both AD and PSAPP mice. These results, along with computer simulations, suggest that Aβ develops neurotoxic properties in vivo when it adopts a fibrillar β-pleated sheet conformation.