Different Amyloid Plaque Structures in Different Forms of Alzheimer's Disease

Alzheimer's is a single defined medical condition that may soon be split into numerous forms, separate named diseases with distinctive differences that happen to look very similar in their later stages. The characteristic changes of Alzheimer's include the accumulation of amyloid-β and altered tau protein in solid depositions in brain tissues, but just as there are different types of tau aggregates involved in the various tauopathies, there may well be subtly different classes of amyloid-β aggregates involved in various forms of Alzheimer's disease.

At the core of Alzheimer's disease are amyloid-beta (Aβ) peptides, which self-assemble into protein fibrils that form telltale plaques in the brain. Now, the results of a study suggest that certain fibril formations are more likely to appear in cases of rapidly progressive Alzheimer's disease, as opposed to less-severe subtypes. The findings increase scientists' understanding of the structure of these fibrils, and may eventually contribute to new tests and treatments for Alzheimer's disease. "It is generally believed that some form of the aggregated Aβ peptide leads to Alzheimer's disease, and it's conceivable that different fibril structures could lead to neurodegeneration with different degrees of aggressiveness. But the mechanism by which this happens is uncertain. Some structures may be more inert and benign. Others may be more inherently toxic or prone to spread throughout the brain tissue."

Prior research has demonstrated that Aβ fibrils with various molecular structures exhibit different levels of toxicity in neuronal cell cultures, a finding confirmed in subsequent mouse trials. One study even demonstrated that Aβ fibrils cultured from patients with rapidly progressive Alzheimer's disease are different in size and resistance to chemical denaturation than those isolated from patients with more slowly progressing disease. Building on these observations, researchers set out to better characterize the structures of these fibrils and get a better handle on the potential correlations between structure and disease subtype. They examined 37 brain tissue samples from 18 deceased individuals - some with rapidly progressive Alzheimer's disease and others who had experienced more common subtypes - with solid-state NMR spectroscopy. The process can be incredibly labor intensive, because solid-state NMR requires milligram-scale quantities of isotopically labeled fibrils. In order to prepare the samples, the team had to amplify and label structures in brain tissue and generate "seeds" - short bits of fibrils - and grow them with synthetic peptides. "You have to make individual samples for individual patients, one by one. It takes about half a year to one year of work. It's not a high-throughput technique. The main barrier is that it's not an easy thing to do and it takes a long time. We were able to look at some 30 tissue samples, and that was really a tour de force."

After examining the solid-state NMR spectra, the researchers found that one specific fibril structure appeared to be statistically correlated with both typical Alzheimer's disease and posterior cortical atrophy Alzheimer's - a condition that involves disruption of visual processing. The researchers also found that range of different fibril structures are statistically correlated with the rapidly progressive disease subtype. "The work shows that distinct clinical presentations of the disease are associated with particular packings of the amyloid beta molecules in the fibrils. Our goal is not really to develop a diagnostic procedure for the clinic. It's to try to understand something fundamental about how the disease develops."

Link: http://www.the-scientist.com/?articles.view/articleNo/47926/title/Forms-of-Alzheimer-s-May-Display-Unique-Plaque-Structures/


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