By Stuart Wolpert
UCLA – August 19, 2019 -- More than
three decades of research on Alzheimer's disease have not produced any major
treatment advances for those with the disorder, according to a UCLA expert who
has studied the biochemistry of the brain and Alzheimer's for nearly 30 years.
"Nothing has worked," said Steven Clarke, a distinguished professor
of chemistry and biochemistry. "We're ready for new ideas." Now,
Clarke and UCLA colleagues have reported new insights that may lead to progress
in fighting the devastating disease.
Scientists have known for years that amyloid
fibrils -- harmful, elongated, water-tight rope-like structures -- form in the
brains of people with Alzheimer's, and likely hold important clues to the
disease. UCLA Professor David Eisenberg and an international team of chemists
and molecular biologists reported in the journal Nature in 2005 that amyloid
fibrils contain proteins that interlock like the teeth of a zipper. The
researchers also reported their hypothesis that this dry molecular zipper is in
the fibrils that form in Alzheimer's disease, as well as in Parkinson's disease
and two dozen other degenerative diseases. Their hypothesis has been supported
by recent studies.
Alzheimer's disease, the most common
cause of dementia among older adults, is an irreversible, progressive brain
disorder that kills brain cells, gradually destroys memory and eventually
affects thinking, behavior and the ability to carry out the daily tasks of
life. More than 5.5 million Americans, most of whom are over 65, are thought to
have dementia caused by Alzheimer's.
The UCLA team reports in the journal
Nature Communications that the small protein beta amyloid, also known as a
peptide, that plays an important role in Alzheimer's has a normal version that
may be less harmful than previously thought and an age-damaged version that is
more harmful.
Rebeccah Warmack, who was a UCLA
graduate student at the time of the study and is its lead author, discovered
that a specific version of age-modified beta amyloid contains a second
molecular zipper not previously known to exist. Proteins live in water, but all
the water gets pushed out as the fibril is sealed and zipped up. Warmack worked
closely with UCLA graduate students David Boyer, Chih-Te Zee and Logan
Richards; as well as senior research
scientists Michael
Sawaya and Duilio Cascio.
What goes wrong with beta amyloid, whose
most common forms have 40 or 42 amino acids that are connected like a string of
beads on a necklace?
The researchers report that with age,
the 23rd amino acid can spontaneously form a kink, similar to one in a garden
hose. This kinked form is known as isoAsp23. The normal version does not create
the stronger second molecular zipper, but the kinked form does.
"Now we know a second water-free
zipper can form, and is extremely difficult to pry apart," Warmack said.
"We don't know how to break the zipper."
The normal form of beta amyloid has six
water molecules that prevent the formation of a tight zipper, but the kink
ejects these water molecules, allowing the zipper to form.
"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.
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.
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