(Image caption: An abnormal protein, left, is intercepted by the UW’s compound that can bind to the toxic protein and neutralize it, as shown at right. Image courtesy: University of Washington)

New protein structure could help treat Alzheimer’s, related diseases

There is no cure for Alzheimer’s disease and other forms of dementia, but the research community is one step closer to finding treatment.

University of Washington bioengineers have designed a peptide structure that can stop the harmful changes of the body’s normal proteins into a state that’s linked to widespread diseases such as Alzheimer’s, Parkinson’s, heart disease, Type 2 diabetes and Lou Gehrig’s disease. The synthetic molecule blocks these proteins as they shift from their normal state into an abnormally folded form by targeting a toxic intermediate phase.

The discovery of a protein blocker could lead to ways to diagnose and even treat a large swath of diseases that are hard to pin down and rarely have a cure.

“If you can truly catch and neutralize the toxic version of these proteins, then you hopefully never get any further damage in the body,” said senior author Valerie Daggett, a UW professor of bioengineering. “What’s critical with this and what has never been done before is that a single peptide sequence will work against the toxic versions of a number of different amyloid proteins and peptides, regardless of their amino acid sequence or the normal 3-D structures.”

The findings were published online this month in the journal eLife.

More than 40 illnesses known as amyloid diseases – Alzheimer’s, Parkinson’s and rheumatoid arthritis are a few – are linked to the buildup of proteins after they have transformed from their normally folded, biologically active forms to abnormally folded, grouped deposits called fibrils or plaques. This happens naturally as we age, to a certain extent – our bodies don’t break down proteins as quickly as they should, causing higher concentrations in some parts of the body.

Each amyloid disease has a unique, abnormally folded protein or peptide structure, but often such diseases are misdiagnosed because symptoms can be similar and pinpointing which protein is present usually isn’t done until after death, in an autopsy.

As a result, many dementias are broadly diagnosed as Alzheimer’s disease without definitive proof, and other diseases can go undiagnosed and untreated.

The molecular structure of an amyloid protein can be only slightly different from a normal protein and can transform to a toxic state fairly easily, which is why amyloid diseases are so prevalent. The researchers built a protein structure, called “alpha sheet,” that complements the toxic structure of amyloid proteins that they discovered in computer simulations. The alpha sheet effectively attacks the toxic middle state the protein goes through as it transitions from normal to abnormal.

The structures could be tailored even further to bind specifically with the proteins in certain diseases, which could be useful for specific therapies.

The researchers hope their designed compounds could be used as diagnostics for amyloid diseases and as drugs to treat the diseases or at least slow progression.

“For example, patients could have a broad first-pass test done to see if they have an amyloid disease and then drill down further to determine which proteins are present to identify the specific disease,” Daggett said.

Green tea and red wine extracts interrupt Alzheimer’s disease pathway in cells

Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer’s disease pathway, according to new research from the University of Leeds.

In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die. They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.

The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer’s disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.

"This is an important step in increasing our understanding of the cause and progression of Alzheimer’s disease," says lead researcher Professor Nigel Hooper of the University’s Faculty of Biological Sciences. "It’s a misconception that Alzheimer’s is a natural part of ageing; it’s a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."

Alzheimer’s disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes. These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.

"We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove," says co-author Dr Jo Rushworth. "And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying."

The team formed amyloid balls in a test tube and added them to human and animal brain cells. Professor Hooper said: “When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells. We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.

"We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle," he added.

Professor Hooper says that the team’s next steps are to understand exactly how the amyloid-prion interaction kills off neurons.

"I’m certain that this will increase our understanding of Alzheimer’s disease even further, with the potential to reveal yet more drug targets," he said.

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, which part-funded the study, said: “Understanding the causes of Alzheimer’s is vital if we are to find a way of stopping the disease in its tracks. While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments. With half a million people affected by Alzheimer’s in the UK, we urgently need treatments that can halt the disease – that means it’s crucial to invest in research to take results like these from the lab bench to the clinic.”