In a new study published in Proceedings of the National Academy of Sciences, researchers 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 the senior author. "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, 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.

The pS8-Aβ₄₀ fibril possesses strong cross-seeding ability to wild-type Aβ₄₀ monomers, while the propagated fibrillar structure shows higher thermodynamic stability and core rigidity compared to the fibrils formed by the self-nucleation of wild-type Aβ₄₀. 

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

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

https://www.cudenvertoday.org/identifying-the-molecular-structure-of-one-of-alzheimers-stickier-culprits/

https://www.pnas.org/content/early/2019/05/14/1818530116