Scientists are hoping to develop a method of counteracting the death of nerve cells in Alzheimer’s disease.
A team led by Professor Bernd Reif of the Technical University of Munich, Germany, took a closer look at the proteins called beta-amyloids that clump together to form long fibrils, or tangles, which cause the death of nerve cells as the disease progresses.
In order to prevent these proteins from clumping together, the scientists used small heat shock proteins, another family of proteins made by cells under stressful conditions. These heat shock proteins were shown in tests to attach to the deformed proteins before they clump together and help restore their proper form.
The scientists used a procedure called solid-state nuclear magnetic resonance spectroscopy (solid-state NMR) to identify sites in heat shock proteins called alpha-B-crystallin that attach to the beta-amyloid. But this process is difficult as alpha-B-crystallin exists in various different forms that are permanently being swapped.
“In addition, it has a large molecular weight,” Reif said. “These factors make structure analysis very difficult.”
Because the process is so challenging, this is “the first direct structure analysis of a heat shock protein during interaction with a bonding partner,” according to the team. Despite the difficulties, the team discovered that in addition to preventing beta-amyloids from forming fibrils, heat shock proteins also “seal” existing fibrils so that further beta-amyloids cannot accumulate.
Although the role these proteins play in neurodegenerative diseases has yet to be nailed down, they are already being considered as agents in new medications. This represents a “new field of application for this versatile helper,” the team says. Small heat shock proteins are “a promising new approach that can be deployed in the treatment of neurodegenerative diseases,” they believe.
The team plans to carry out further research on a region of alpha-B-crystallin that binds protein types that, unlike the beta-amyloid, clump together in an unordered manner. Their work is published in the journal Nature Structural Molecular Biology.
One particular heat shock protein, called heat shock protein 70 (HSP70), has been the focus of many studies. A team from Qingdao University in China reviewed the findings to date. They say, “HSP70 attracts extensive attention worldwide, because it plays a crucial role in preventing protein misfolding in Alzheimer’s disease.”
They explain that HSP70 is present in almost all parts of the human cell, where it protects proteins from misfolding and repairs damaged proteins. In lab tests, brain cells that were programmed to make extra HSP70 did not show the abnormal folding of beta-amyloids that triggers Alzheimer’s.
Furthermore, HSP70 helps prevent the increased rate of brain cell death seen in postmortem tissues from individuals with Alzheimer’s disease. This increased cell death is due to buildup of beta-amyloids and oxidative stress. Overall, there are two main ways in which HSP70 could be used to treat Alzheimer’s disease: by raising the body’s own HSP70 levels, or by raising HSP70 via medications.
The experts write, “Numerous studies have indicated that HSP70 could suppress the progression of Alzheimer’s disease. Thus, targeting HSP70 might represent a promising strategy for the treatment of Alzheimer’s disease.”
However, some limitations must be overcome before heat shock proteins can be used with patients. For example, the effects of giving HSP70 are unpredictable because the appropriate dose is unknown.
“On the whole, further studies will be required to fully elucidate the roles of HSP70 in Alzheimer’s disease,” writes the Qingdao research team. But, “This might bring the hope of conquering Alzheimer’s disease eventually.”
Experts from the University of Catania, Italy, agree. Professor Vittorio Calabrese and colleagues state, “As one of the most important neurodegenerative disorders, Alzheimer’s disease is a progressive disorder with cognitive and memory decline, speech loss, personality changes and synapse loss.
“With the increasingly aging population of the United States, the number of Alzheimer’s disease patients is predicted to reach 14 million in the mid-21st century in the absence of effective interventions. This will pose an immense economic and personal burden on the people of this country.”
The team adds that there is now strong evidence to suggest that factors such as disturbed protein metabolism are central to Alzheimer’s disease. Raising levels of HSP70 is one potentially successful approach, they believe.
Scientists from New York University are currently working on the best ways to test drugs to increase the body’s HSP70 levels, in order to eliminate abnormal beta-amyloid. They report that “attempts to target some of these heat shock proteins have so far been unsuccessful, while others are currently in various developmental stages.”
Efforts to determine the potential of HSP70 include a range of lab tests using mammalian, yeast, or bacterial cultures. The team is working to create a novel method that can demonstrate the effect of HSP70, with the aim of efficiently identifying the best formulation for human clinical trials.
Mainz, A. et al. The Chaperone alpha B-Crystallin Deploys Different Interfaces to Capture an Amorphous and an Amyloid Client. Nature Structural Molecular Biology, 12 October 2015 doi: 10.1038/nsmb.3108
Lu, R. C. et al. Heat shock protein 70 in Alzheimer’s disease. BioMed Research International, 6 November 2014 doi: 10.1155/2014/435203
Dattilo, S. et al. Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases. Immunity & Ageing. 4 November 2015 doi: 10.1186/s12979-015-0046-8
Repalli, J. and Meruelo, D. Screening strategies to identify HSP70 modulators to treat Alzheimer’s disease. Drug Design, Development and Therapy. 7 January 2015 doi: 10.2147/DDDT.S72165