Credit: JACS

Two research teams have independently obtained atomic-resolution structures of fully formed amyloid-β peptide fibrils that may be involved in Alzheimer’s disease. These fibrils or similar ones form aggregates called “senile plaques” in the brains of patients with the memory- and identity-loss disease.

The fibrils the teams studied are made of a 42-amino-acid peptide, Aβ-42, which is one of two major forms of amyloid-β peptide. It is more neurotoxic, aggregates faster, and is more predominant in senile plaques than the other type, Aβ-40. Scientists have structurally analyzed Aβ-40 fibrils before. But structural analysis of full Aβ-42 fibrils—thought to be the main bad actors in Alzheimer’s disease and therefore the more important of the two types—has been elusive.

Advances in magic-angle spinning nuclear magnetic resonance spectroscopy and laborious efforts to prepare pure fibril samples enabled the teams to almost simultaneously determine structures of the full Aβ-42 fibril, which forms as a dimer. The structures could make it easier for researchers to design antibodies and small-molecule drugs that prevent fibril formation or dissolve fibrils that have already formed.

Robert G. Griffin at Massachusetts Institute of Technology, Sara Linse at Lund University, and coworkers carried out one of the studies (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b05129). And Anja Böckmann of the University of Lyon, Beat H. Meier and Roland Riek of the Swiss Federal Institute of Technology, Zurich, and coworkers were responsible for the other (Proc. Natl. Acad. Sci. USA 2016, DOI: 10.1073/pnas.1600749113).

“People have waited impatiently for 110 years, since Alois Alzheimer diagnosed his first patient, to understand the molecular and structural basis of Alzheimer’s disease,” says Shuguang Zhang, also at MIT, who has studied peptide-fibril formation but wasn’t involved in the recent work. The new structures could help researchers identify drugs “to delay or prevent the terrible and devastating disease.”

The studies show that Aβ-42 peptides on one side of the dimeric fibril adopt an S-shaped conformation and interact hydrophobically with S-shaped peptides oriented symmetrically on the other side. The S-shaped structure is essentially the same determined last year for an Aβ-42 fibril subunit—one half of the full dimeric Aβ-42 fibril—by Yoshitaka Ishii at the University of Illinois, Chicago, and coworkers (Nat. Struct. Mol. Biol. 2015, DOI: 10.1038/nsmb.2991 and C&EN, May 18, 2015, page 6). The three studies thus suggest that the S-shape is a consensus structure for Aβ-42 fibrils.

“The new results confirm Ishii’s work and also reveal the molecular-level details of contacts” between adjacent peptides on the two halves of the fibril, says amyloid fibril expert Robert Tycko of the National Institute of Diabetes & Digestive & Kidney Diseases.

With the new structures in hand, “There are Avogadro’s number of follow-up experiments to do,” Griffin says, including studying fibrils formed by mutant Aβ-peptides that cause early-onset Alzheimer’s disease and finding agents that bind to Aβ42. “This will keep us busy for another decade or two,” he says.

This article has been translated into Chinese and can be found here.