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Research teams characterize complete Alzheimer’s fibrils

Studies provide atomic-level view of full dimeric fibrils of key Alzheimer’s-related peptide

by Stu Borman
July 26, 2016

Credit: JACS
The Griffin group’s ribbon representation of the Aβ-42 fibril structure, in rainbow colors, shows how Aβ-42 peptides align symmetrically along the dimeric fibril axis. Arrows are β-strands, and threads are loops and turns.

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.

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Robert M. Metzger (July 27, 2016 2:54 PM)
Any hope for the amyloid plaques that form in AL amyloidosis? I suspect the proteins involved in amyloidosis are different. Amyloidosis is such a rare disease (but my wife suffers from it): in amyloidosis the beta-pleated sheet conformations are abnormally chosen (instead of random-coil) during protein synthesis in bone marrows.... Help !!!!
Joseph E. Wreen Ph.D. (July 27, 2016 4:24 PM)
Excess copper appears to cause the mutant Abeta peptide. If so, I found that the compounds in Asparagus may help. I have Parkinson and asparagus relieves my tremors for 5 to 10 hours. I note the work of Dr. Brewer who since 2003 cited Copper as a potential cause of Alzheimer and Dr. Squitti of Rome, Italy who recommends a low copper diet for Alzheimer. I have prepared an essay for the prep of asparagus and references to the research. For a free copy via email write me at .
Thank You J. Wreen Ph.D. Inorganic Chem Ga. Tech 1974

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