Understanding the process of fibril formation and, more specifically, the toxic beta amyloid (Aβ) protein fragments, is fundamental to advancing treatments for Alzheimer’s disease. New research investigates the structure and dynamics of a pathologically relevant posttranslational modified Aβ, the aggressive, “seeding-prone” Ser-8-phosphorylated Aβ40 (pS8-Aβ40).
In a study published in Proceedings of the National Academy of Sciences, entitled “Molecular structure of an N-terminal phosphorylated β-amyloid fibril” researchers from the University of Colorado, Denver, and Binghamton University mapped the molecular structure and dynamics of an aggressive protein modification that spurs on Alzheimer’s disease.
“Roughly 10% of Alzheimer’s disease cases are the result of identified mutations,” said Liliya Vugmeyster, PhD, associate professor in the department of chemistry at the University of Colorado, Denver. “But 90% 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 when Aβ clump, forming 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.
The study targeted the structure and the dynamics of the aggressive, “seeding-prone” Ser-8-phosphorylated 40-residue Aβ (pS8-Aβ40) fibrils, reporting the molecular structure. The authors wrote that “the N-terminal structures in pS8-Aβ40 fibril differ significantly from all known wild-type Aβ40 fibrils, with strong intra-strand interactions that make the N terminus associated closely with the amyloid core.”
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. Even when it existed in smaller amounts, pS8-Aβ40 acted as the alpha in structure polymorphism. In addition, the pS8-Aβ40 had a higher level of cellular toxicity compared to other fibrils. And, the N-terminus, the creation point of the protein, played an important role in manipulating both the fibrils structures and the aggregation processes.
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,” said Vugmeyster. “Whatever you do to them in the test tubes, they adjust, find a way to go into a toxic state and aggregate.”
The authors conclude that the molecular architectures of Aβ pathological plaques, and the underlying fibrillar structures, may be different among AD subtypes. Also, they note that their current and previous work suggests that the quantities of certain Aβ species do not necessarily correlate with their neuronal cellular toxicities. Lastly, that the molecular structure of pS8-Aβ40 fibril highlighted the significance of the N terminus in manipulating both the fibrils structures and the aggregation processes.
Vugmeyster said mapping the structure of pS8-Aβ40 is just the first piece of a larger puzzle and hopes this information might one day lead to ideas of how to come up with drugs that can break the vicious cycle of cell degeneration.
