Aβ42 is More Rigid than Aβ40 at the C Terminus: Implications for Aβ Aggregation and Toxicity

Aβ40 and Aβ42 are the major forms of amyloid β peptides (Aβ) in the brain. Although Aβ42 differs from Aβ40 by only two residues, Aβ42 is much more prone to aggregation and more toxic to neurons than Aβ40. To probe whether dynamics contribute to such dramatic difference in function, backbone ps–ns dynamics of native Aβ monomers were characterized by 15N spin relaxation at 273.3 K and 800 MHz. Aβ42 aggregates much faster than Aβ40 in the NMR tube. The effect of Aβ aggregation was removed from the relaxation measurement by interleaved data collection. R1, R2 and nuclear Overhauser enhancement (NOE) values are similar in Aβ40 and Aβ42, except at the C terminus, indicating Aβ42 and Aβ40 monomers have identical global motions. Comparisons of the spectral density function J(0.87ωH) and order parameters (S2) indicate that the Aβ42 C terminus is more rigid than the Aβ40 C terminus. At 280.4 K and 287.6 K, the Aβ42 C terminus remains more rigid than the Aβ40 C terminus, suggesting such a dynamical difference is likely present at the physiological temperature. The Aβ42 monomer likely has less configurational entropy due to restricted motion in the C terminus and may pay a smaller entropic price to form fibrils than the Aβ40 monomer. We hypothesize that the entropic difference between Aβ40 and Aβ42 monomers might partly account for the fact that Aβ42 is the major Aβ species in parenchymal senile plaques in most Alzheimer's diseased brains in spite of the predominance of Aβ40 in plasma. The increased rigidity of the Aβ42 C terminus is likely due to its pre-ordering for β-conformation present in soluble oligomers and fibrils. The Aβ42 C terminus may therefore serve as an internal seed for aggregation.