Aβ42 is more rigid than Aβ40 at the C terminus:: Implications for Aβ aggregation and toxicity

A beta 40 and A beta 42 are the major forms of amyloid beta pepticles (A beta) in the brain. Although A beta 42 differs from A beta 40 by only two residues, A beta 42 is much more prone to aggregation and more toxic to neurons than A beta 40. To probe whether dynamics contribute to such dramatic difference in function, backbone ps-ns dynamics of native A beta monomers were characterized by N-15 spin relaxation at 273.3 K and 800 MHz. A beta 42 aggregates much faster than A beta 40 in the NMR tube. The effect of A aggregation was removed from the relaxation measurement by interleaved data collection. R-1, R-2 and nuclear Overhauser enhancement (NOE) values are similar in, A beta 40 and A beta 42, except at the C terminus, indicating A beta 42 and A beta 40 monomers have identical global motions. Comparisons of the spectral density function J(0.87 omega(H)) and order parameters (S-2) indicate that the A beta 42 C terminus is more rigid than the A beta 40 C terminus. At 280.4 K and 287.6 K, the A beta 42 C terminus remains more rigid than the A beta 40 C terminus, suggesting such a dynamical difference is likely present at the physiological temperature. The A beta 42 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 A beta 40 monomer. We hypothesize that the entropic difference between A beta 40 and A beta 42 monomers might partly account for the fact that A beta 42 is the major A beta species in parenchymal senile plaques in most Alzheimer's diseased brains in spite of the predominance of A beta 40 in plasma. The increased rigidity of the A beta 42 C terminus is likely due to its pre-ordering for beta-conformation present in soluble oligomers and fibrils. The A beta 42 C terminus may therefore serve as an internal seed for aggregation. (c) 2006 Elsevier Ltd. All rights reserved.