Published:
6/16/2015

Researchers at the Frederick National Lab (FNL) have collaborated in solving the three-dimensional structure of a key protein in Alzheimer’s disease, providing new insight into the basic mechanisms that give rise to the devastating illness.

The protein—amyloid-beta(1-42)—is the initial and most common protein that builds up layer by layer in spaces between nerve cells of the brain in patients with Alzheimer’s. This buildup contributes to a progressive loss of brain function that is ultimately fatal.

The structural details of the amyloid-beta(1-42) fibril reveal for the first time a characteristic S-shape, compared with the U-shape of the previously characterized amyloid-beta(1-40) fibril. Images courtesy of Buyong Ma, Laboratory of Experimental Immunology.

Knowing the structure of this amyloid beta protein makes it possible to begin understanding more fully how it contributes to the disease and how that contribution might be halted by a specific drug or other therapy.

The normal role of amyloid beta proteins is not well understood, but fragments of these proteins—such as amyloid-beta(1-42)—can contain flaws (improper folding) that cause them to clump together and accumulate around nerve cells.

The normal role of amyloid beta proteins is not well understood, but fragments of these proteins—such as amyloid-beta(1-42)—can contain flaws (improper folding) that cause them to clump together and accumulate around nerve cells.

“This study represents only the first step toward revealing previously unknown structural details and structural variations of amyloid-beta(1-42) fibrils, which are likely to be more relevant to the pathology of AD [Alzheimer’s disease] than well-studied amyloid-beta(1-40) fibrils,” the researchers wrote in the May 4 online edition of the journal Nature Structural & Molecular Biology.

The amyloid-beta(1-42) structure presents several distinctive characteristics, among them: three sheets of amino acids folded upon themselves in an “S” shape, rather than the double-folded amyloid-beta(1-40), and a salt bridge joining one bend in the S-shaped loop with a tail-end of the fibril. These and other features give a new perspective on the relationship between this particular type of structure and the behavior of amyloid proteins in Alzheimer’s disease.

The senior author on the paper is Yoshitaka Ishii of the University of Illinois at Chicago. Collaborators include Buyong Ma, Ph.D., senior scientist, and Ruth Nussinov, Ph.D., senior investigator, Laboratory of Experimental Immunology, FNL. In 2002, Ma and Nussinov revealed for the first time the key structural features of the currently well-known amyloid-beta(1-40) protein fibril structure.

In the current research, Ishii’s group measured the chemical shifts using solid-state nuclear magnetic resonance (ssNMR) for the amyloid-beta(1-42) fibril. However, the conventional method had difficulty decoding the structure. Ishii then collaborated with the FNL investigators, who solved the structure computationally based on the ssNMR data. Ma did the computational work using a new approach. The final structure was slightly refined by Ishii’s group based on FNL structural modeling. The FNL group had predicted the new salt bridge feature of the protein, which was subsequently confirmed by Ishii’s group through isotope labeling.

Top image: The structural details of the amyloid-beta(1-42) fibril reveal for the first time a characteristic S-shape, compared with the U-shape of the previously characterized amyloid-beta(1-40) fibril. Images courtesy of Buyong Ma, Laboratory of Experimental Immunology.

Last updated: June 23, 2015