One of the hallmarks of Alzheimer’s disease is the abnormal clumping of beta-amyloid proteins in the brain, resulting in the death of brain cells. The discovery that small heat shock proteins prevent uncontrolled protein clumping has opened the possibility of developing drugs that emulate this effect. Now, a new study takes this a step further by revealing how small heat shock proteins interact with beta-amyloid to prevent clumping.

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These electron microscope images show beta-amyloid in the absence (left) and presence (right) of alphaB-crystallin.
Image credit: Andi Mainz/TUM

The researchers, from the Technical University of Munich (TUM) and the Helmholtz Zentrum München, both in Germany, report their findings in the journal Nature Structural & Molecular Biology.

Small heat shock proteins are “helper” or “chaperone” proteins that perform a variety of roles, including the guarding of other proteins during times of stress to stop them becoming abnormal, such as folding into the wrong shape or clumping when they should not.

One reason to understand these helper proteins is the hope of using them as agents in the treatment of brain-wasting diseases such as Alzheimer’s. Small heat shock proteins attach themselves to the deformed proteins before they start to aggregate and keep them in a soluble state – thus preventing the clumping.

In the case of Alzheimer’s disease, the heat shock protein that stops beta-amyloid aggregating to form long fibrils that clog up brain cells is called alpha-B-crystallin. Other heat shock proteins are associated with neurodegenerative diseases such as Parkinson’s disease and multiple sclerosis.

In the new study, a team led by Bernd Reif, a chemistry professor at TUM and a group leader at the Helmholtz Zentrum München, reveals precisely how the structure of alpha-B-crystallin interacts with beta-amyloid to prevent the clumping that is seen in Alzheimer’s.

Using solid-state nuclear magnetic resonance (NMR) spectroscopy, the researchers identified the exact sites in the alpha-B-crystallin structure that attach to the beta-amyloid. The achievement is the result of painstaking work because of the challenges posed by the complexity of alpha-B-crystallin, as Prof. Reif explains:

Alpha-B-crystallin exists in various different forms comprising 24, 28 or 32 subunits that are permanently being swapped. In addition, it has a large molecular weight. These factors make structure analysis very difficult.”

The team found that alpha-B-crystallin uses two features of its structure to block the aggregation process. One feature allows it to attach to individual beta-amyloids to prevent them clumping into fibrils, and the other “seals” already-formed fibrils to prevent them adding more amyloids.

The discovery offers a model for researchers interested in engineering proteins that emulate these alpha-B- crystallin features to bind specifically to beta-amyloid and similar proteins.

The study follows earlier research that Medical News Today reported in March 2014 where a team led by another TUM member also found that heat shock proteins influence the aggregation of tau proteins – another hallmark of Alzheimer’s.