New Insights into What May Go Awry in Brains of People with Alzheimer’s

“Rebeccah has shown this kink leads to faster growth of the fibrils that have been linked to Alzheimer’s disease,” said Clarke, who has conducted research on biochemistry of the brain and Alzheimer’s disease since 1990. “This second molecular zipper is double trouble. Once it’s zipped, it’s zipped, and once the formation of fibrils starts, it looks like you can’t stop it. The kinked form initiates a dangerous cascade of events that we believe can result in Alzheimer’s disease.”

Why does beta amyloid’s 23rd amino acid sometimes form this dangerous kink?

Clarke thinks the kinks in this amino acid form throughout our lives, but we have a protein repair enzyme that fixes them.

“As we get older, maybe the repair enzyme misses the repair once or twice,” he said. “The repair enzyme might be 99.9% effective, but over 60 years or more, the kinks eventually build up. If not repaired or if degraded in time, the kink can spread to virtually every neuron and can do tremendous damage.”

“The good news is that knowing what the problem is, we can think about ways to solve it,” he added. “This kinked amino acid is where we want to look.”

The research offers clues to pharmaceutical companies, which could develop ways to prevent formation of the kink or get the repair enzyme to work better; or by designing a cap that would prevent fibrils from growing.

Clarke said beta amyloid and a much larger protein tau — with more than 750 amino acids — make a devastating one-two punch that forms fibrils and spreads them to many neurons throughout the brain. All humans have both beta amyloid and tau. Researchers say it appears that beta amyloid produces fibrils that can lead to tau aggregates, which can spread the toxicity to other brain cells. However, exactly how beta amyloid and tau work together to kill neurons is not yet known.

 Research by UCLA professor Steven Clarke and former graduate student Rebeccah Warmack, as well as UCLA colleagues, reveals new information about the brain’s biochemistry.

Credit: Reed Hutchinson/UCLA

In this study, Warmack produced crystals, both the normal and kinked types, in 15 of beta amyloid’s amino acids. She used a modified type of cryo-electron microscopy to analyze the crystals. Cryo-electron microscopy, whose development won its creators the 2017 Nobel Prize in chemistry, enables scientists to see large biomolecules in extraordinary detail. Professor Tamir Gonen pioneered the modified microscopy, called microcrystal electron diffraction, which enables scientists to study biomolecules of any size.

Eisenberg is UCLA’s Paul D. Boyer Professor of Molecular Biology and a Howard Hughes Medical Institute investigator. Other researchers are co-author Gonen, a professor of biological chemistry and physiology at the UCLA David Geffen School of Medicine and a Howard Hughes Medical Institute investigator; and Jose Rodriguez, assistant professor of chemistry and biochemistry who holds the Howard Reiss Career Development Chair.

The research was funded by the National Science Foundation, National Institutes of Health, Howard Hughes Medical Institute, and the UCLA Longevity Center’s Elizabeth and Thomas Plott Chair in Gerontology, which Clarke held for five years.

Contacts and sources:
Stuart Wolpert
University of California – Los Angeles

Citation: Structure of amyloid-β (20-34) with Alzheimer’s-associated isomerization at Asp23 reveals a distinct protofilament interface.
Rebeccah A. Warmack, David R. Boyer, Chih-Te Zee, Logan S. Richards, Michael R. Sawaya, Duilio Cascio, Tamir Gonen, David S. Eisenberg, Steven G. Clarke. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-019-11183-z