Alzheimer’s disease: protective gene uncovered in human cell model bringing promise for new drug discoveries – The Conversation UK

Every three seconds, someone in the world develops dementia. The most common form of dementia is Alzheimers disease. While researchers have identified a number of risk factors that are linked to dementia including genetics, smoking, and high blood pressure there is currently still no cure.

Part of the reason for this is because of how complicated it is to test potential Alzheimers drugs. In order to conduct clinical trials participants need to have symptoms. But by the time symptoms appear, its usually too late for treatments to have a large effect as many of their brain cells have already died.

But our latest research developed a new human cell model that is able to rapidly simulate the development of Alzheimers disease in the lab. This allowed us to identify a gene, called BACE2, that is naturally able to suppress the signs of Alzheimers disease in human brain cells. Our research is the result of around five years work, and was the collaborative effort of teams based in London, Singapore, Sweden and Croatia.

Researchers already know a lot about which genes cause Alzheimers disease or make someone more likely to develop it. These genes contribute to certain toxic proteins accumulating in the human brain. So our team thought that the opposite must also be true: our brain cells must also have proteins that can naturally slow down the development of Alzheimers.

One gene that can definitely cause Alzheimers disease is a gene found on the 21st pair of human chromosomes that is responsible for making the amyloid precursor protein (APP). Research shows that 100% of people born with just one extra copy of the APP gene (called DupAPP) will develop dementia by age 60.

People with Downs syndrome are born with three copies of APP because they have a third 21st chromosome. But by age 60, only 60% of them will develop clinical dementia. We wanted to know why some people with Downs syndrome have delayed development of or never develop Alzheimers dementia compared to those who have one extra DupAPP gene.

The simple answer for this is because they have an extra dose of all other genes located in chromosome 21. We believed that there could be some dose-sensitive genes on chromosome 21 that, when triplicated, protect against Alzheimers disease by counteracting the effects of the third APP gene.

These genes must then appear to delay the onset of clinical dementia in some people with Downs syndrome by approximately 20 years. Studies have even shown that any future drug able to delay dementia onset by just five years would reduce the prevalence of Alzheimers in the general population by half.

To study the potential of the extra genes, we took hair follicle cells from people with Downs syndrome and re-programmed the cells to become like stem cells. This allowed us to turn them into brain cells in a Petri dish.

We then grew them into 3D balls of cells that imitated the tissue of the grey matter (cortex) of the human brain. The 3D nature of the culturing allowed misfolded and toxic proteins to accumulate, which are crucial changes that lead to Alzheimers disease in the brain.

We found all three major signs of Alzheimers disease (plaque build-up in the brain, misfolded tau proteins and dying brain neurons) in cell cultures from 71% of people with Downs syndrome who donated samples. This proportion was similar to the percentage of clinical dementia among adults with Downs syndrome.

We were also able to use CRISPR a technology that allows researchers to alter DNA sequences and modify a genes function to reduce the number of BACE2 genes from three copies to two copies on chromosome 21. This was only done in cases where there were no indications of Alzheimers disease in our cellular model. Surprisingly, reducing the number of BACE2 genes on chromosome 21 provoked signs of the disease. This strongly suggest that having extra copies of a normal BACE2 gene could prevent Alzheimers.

The protective action of BACE2 reduces the levels of toxic amyloid proteins. This was verified in our cellular models, as well as in cerebrospinal fluid and post-mortem brain tissue from people with Downs syndrome.

Our study provides proof that natural Alzheimers-preventing genes exist, and now we have a system to detect new potential protective genes. Importantly, recent research showed the protective action of BACE2 might also be relevant to people who dont have Downs syndrome.

Our results also show that all three signs of Alzheimers disease can be potentially detected in cells from live donors. Though this requires a lot more research, it means we may be able to develop tests that identify which people are at higher risk of Alzheimers disease by looking at their cells.

This would allow us to detect the disease before it starts developing in a persons brain, and could make it possible to design personalised preventative treatments. However, we are still a long way from reaching this goal.

Most importantly, our work shows that all three signs of Alzheimers disease detected using our model could be prevented by drugs known to inhibit the production of the toxic amyloid protein and this can be detected in as little as six weeks in the lab. We hope our discovery could lead to the development of new drugs aimed at delaying or preventing Alzheimers disease, before it causes brain cell death.