Alzheimer’s disease fibrils keep their shape

September 12, 2013 § Leave a comment

Molecular structure of amyloid fibrils from patient 1. Image provided by Robert Tycko.

Molecular structure of amyloid fibrils from patient 1. Image provided by Robert Tycko.

One telltale sign of Alzheimer’s disease is the finding of clumps of a protein called beta-amyloid (Aβ) in the brain of a patient during autopsy. This protein forms fibrils with different structures, which go on to multiply and clump together. In a paper just out in Cell, researchers studied fibrils taken from two Alzheimer’s patients and discovered that the structure of a fibril persists as the fibril seeds the formation of more fibrils. The work has implications for the development for diagnostic and therapeutic approaches.

It’s possible to grow Aβ fibrils in test tubes by using synthetic Aβ peptides. But when that’s done, researchers get a mishmash of different fibril structures. When they realized this, Robert Tycko at the National Institute of Diabetes and Digestive and Kidney Diseases says he and his colleagues “began to wonder which structures actually form in brain tissue of Alzheimer’s disease patients.”

Tyko’s team in collaboration with that of Steven Meredith at the University of Chicago identified two patients who had different diagnoses for their dementia when they were alive. One patient was diagnosed initially with Lewy body dementia, but when she died and her brain was autopsied, pathologists found an abundance of Aβ clumps. The other patient was diagnosed with Alzheimer’s disease in the first place.

The investigators extracted Aβ fibrils from brain tissue samples of these two patients and used the fibrils as seeds to grow more fibrils in test tubes. They analyzed the fibrils by solid-state nuclear magnetic resonance and electron microscopy and showed that fibrils from each patient had highly uniform molecular structures.  There wasn’t a mishmash of different fibril structures. More importantly, the fibrils from the two patients were distinctly different from each other in molecular structure.

Tycko explains this finding may mean that “different Alzheimer’s disease patients can develop different fibril structures in their brains.  Results in this paper provide the first evidence that structural variations within Aβ fibrils may correlate with variations in clinical history.  This possibility needs to be examined carefully in future studies.”

The work also suggests that any diagnostic or therapeutic approaches need to be carefully tailored to the fibril structure. “Since specific fibril structures develop in Alzheimer’s disease brains, rather than a heterogeneous mixture of structures, it is important to develop amyloid-binding compounds for diagnostic imaging that target these specific structures,” says Tycko. “It may also be productive to design compounds that inhibit the formation of specific fibril structures, if certain structures, but not others, turn out to be more neurotoxic.”

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