Eurasia Review: Identifying Molecular Structure Of One Of Alzheimer’s Stickier Culprits

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In a new study published in Proceedings of the National Academy of Sciences, researchers from the University of Colorado Denver and Binghamton University are the first to map the molecular structure and dynamics of an aggressive protein modification that spurs on Alzheimer’s disease.

“Roughly ten percent of Alzheimer’s disease cases are the result of identified mutations,” says Liliya Vugmeyster, PhD, associate professor in the department of chemistry, College of Liberal Arts & Sciences, at CU Denver. “But 90 percent of Alzheimer’s cases are not explained by these mutations, which is why we need to understand the molecular base of the disease.”

Alzheimer’s disease begins decades before the onset of symptoms.
It starts the day microscopic, toxic protein fragments called beta
amyloids (Aβ) glom onto each other. Those clumps form chains called
fibrils, which band together to become a sticky, pleated sheet that
builds on brain cells like plaque. As it accumulates, the plaque
disrupts cell membranes and the communication between brain cells,
causing them to die. Until now, understanding just the molecular makeup
of the proteins – and the more aggressive subtypes that cause a rapid
acceleration of the disease – has plagued researchers.

In this collaborative study with Wei Qiang, assistant professor
of biophysical chemistry at Binghamton University, researchers targeted
the structure and the dynamics of the aggressive, “seeding-prone”
Ser-8-phosphorylated 40-residue Aβ (pS8-Aβ40) fibrils. They found that
even when it existed in smaller amounts, pS8-Aβ40 acted as the alpha in
structure polymorphism. It also had a higher level of cellular toxicity
compared to other fibrils. In looking at the molecular structure,
researchers found that the N-terminus, the creation point of the
protein, played an important role in manipulating both the fibrils
structures and the aggregation processes.

Vugmeyster, along with student Dan Fai Au, M.S., and Dmitry
Ostrovsky, instructor in mathematical and statistical sciences, studied
the flexibility of the fibrils. In previous research, Vugmeyster found
that flexibility could be part of the control mechanism for plaque
accumulation.

“Fibrils are very resilient to treatment that prevents
aggregation,” says Vugmeyster. “Whatever you do to them in the test
tubes, they adjust, find a way to go into a toxic state and aggregate.”

Vugmeyster says mapping the structure of pS8-Aβ40 is just the
first piece of a larger puzzle. Qiang’s group at Binghampton and her
team plan do the same for several important protein modifications,
focusing on the static structure, dynamics and stability of each.
Eventually, she says, this information might one day lead to ideas how
to come up with drugs that can break the vicious cycle of cell
degeneration.

Eurasia Review


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