‘Protective’ form of Alzheimer’s protein could help shield brain cells from damage, Sheffield research finds

A University of Sheffield researcher is investigating how proteins linked to Alzheimer’s disease damage nerve cells, with the aim of identifying new ways to protect the brain in the early stages of the disease.

Emma Garland, Research Associate, is part of a research team led by Dr Suman De, Senior Research Fellow, investigating why one form of a protein called amyloid beta is more harmful to nerve cells than another – and whether changing the balance between the two could help prevent damage.

Amyloid beta is a protein naturally found in the brain. It normally exists in small amounts, but in Alzheimer’s disease some forms can build up and stick together, forming structures called plaques. These plaques are a hallmark of Alzheimer’s disease and are associated with damage to nerve cells, which are responsible for transmitting information around the brain.

There are several forms of amyloid beta, including amyloid beta 40 and amyloid beta 42. Although they are very similar, the two forms appear to have different effects on nerve cells.

“Amyloid beta 40 is abundant in the healthy brain and is considered less harmful, whereas amyloid beta 42 is increased in Alzheimer’s disease, causing toxic damage that leads to nerve cell death,” explains Emma.

Her research is focused on understanding why amyloid beta 42 is particularly damaging, and whether that damage can be stopped.

“We are trying to better understand why amyloid beta 42 is more harmful to nerve cells in disease and whether we can stop this harm for potential therapeutic use in early disease stages,” she said.

To investigate this, Emma and her colleagues use human stem cells. Stem cells are cells that have the ability to develop into different types of cells in the body. In the laboratory, researchers use them to produce nerve cells, allowing them to study what happens to these cells when exposed to different forms and amounts of amyloid beta.

The team also uses genetically engineered cells to investigate the role of APOE, a gene involved in Alzheimer’s disease risk. They compare cells carrying APOE4, a version of the gene associated with an increased risk of Alzheimer’s, with cells carrying APOE3, a more common version that is not associated with the same increased risk.

This allows the researchers to investigate whether a person’s genetic background affects how their nerve cells respond to different ratios of amyloid beta 40 and amyloid beta 42.

Emma is also working with donated human brain tissue from people who had Alzheimer’s disease and from people who were neurologically healthy. This provides an opportunity to compare what happens in laboratory models with what can be seen in human brains.

Using a technique called immunohistochemistry, the team can identify specific proteins in brain tissue by applying specially designed stains that make them visible under a microscope. This allows the researchers to examine how much amyloid beta 42 is present within the plaques found in Alzheimer’s disease.

The research has already produced findings that point towards a potentially important protective role for amyloid beta 40.

The team found that a higher ratio of amyloid beta 42 relative to amyloid beta 40 significantly increases toxicity to nerve cells. Analysis of human brain tissue also confirmed that disease-related amyloid plaques consist predominantly of amyloid beta 42.

Crucially, the researchers found that increasing levels of amyloid beta 40 reduces the toxic effects caused by amyloid beta 42.

“Our data shows that increasing levels of amyloid beta 40 reduces the toxic effects caused by amyloid beta 42, opening an exciting new route for potential therapies,” said Emma.

The findings could help researchers understand not only how Alzheimer’s disease causes damage, but also how that damage might be prevented before widespread loss of nerve cells occurs.

“Alzheimer’s disease currently lacks treatments that can stop or prevent nerve cell loss,” said Emma. “By uncovering how specific protein interactions cause cell damage, this research can help identify precise targets to intervene early on in disease – before widespread brain damage occurs.”

The long-term hope is that re-balancing amyloid beta protein levels could form the basis of early-stage preventative treatments that slow or stop the progression of Alzheimer’s disease.

For Emma, the potential impact of the work extends beyond Alzheimer’s. The stem cell models and techniques being developed through the project could also help researchers investigate other neurodegenerative diseases – conditions in which nerve cells become damaged or die over time.

“Understanding the key mechanisms that cause neurodegenerative diseases, such as Alzheimer’s disease, will allow us to find better treatments and improve the lives of people living with these devastating diseases,” she said.

Emma works alongside Agnieszka Urbanek, postdoctoral researcher and Harry Baker, PhD student as part of Dr Suman De’s research team, studying stem cells, nerve cells, and the genetic and protein mechanisms underlying Alzheimer’s disease.

The research is funded by a UKRI Future Leaders Fellowship and aims to build a better understanding of the early biological processes that drive Alzheimer’s disease, bringing researchers closer to identifying ways to protect nerve cells before irreversible damage occurs.