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



Our method could someday potentially detect the disease before it starts developing in a person’s brain.
Robert Kneschke/ Shutterstock

Dean Nizetic, Queen Mary University of London

Every three seconds, someone in the world develops dementia. The most common form of dementia is Alzheimer’s 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 Alzheimer’s drugs. In order to conduct clinical trials participants need to have symptoms. But by the time symptoms appear, it’s 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 Alzheimer’s disease in the lab. This allowed us to identify a gene, called BACE2, that is naturally able to suppress the signs of Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s.

One gene that can definitely cause Alzheimer’s 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 Down’s 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 Down’s syndrome have delayed development of – or never develop – Alzheimer’s 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 Alzheimer’s 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 Down’s 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 Alzheimer’s in the general population by half.

We re-programmed cells, turning them into brain cells.
arrideo/ Shutterstock

To study the potential of the extra genes, we took hair follicle cells from people with Down’s 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 Alzheimer’s disease in the brain.

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

We were also able to use CRISPR – a technology that allows researchers to alter DNA sequences and modify a gene’s 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 Alzheimer’s 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 Alzheimer’s.

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 Down’s syndrome.

Our study provides proof that natural Alzheimer’s-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 don’t have Down’s syndrome.

Our results also show that all three signs of Alzheimer’s 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 Alzheimer’s disease by looking at their cells.

This would allow us to detect the disease before it starts developing in a person’s 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 Alzheimer’s 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 Alzheimer’s disease, before it causes brain cell death.The Conversation

Dean Nizetic, Professor of Cellular and Molecular Biology, Queen Mary University of London

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Are there certain foods you can eat to reduce your risk of Alzheimer’s disease?



Eating healthy foods doesn’t just improve our physical health. It can benefit our mental health, too.
From shutterstock.com

Ralph Martins, Macquarie University

With the rise of fad diets, “superfoods”, and a growing range of dietary supplement choices, it’s sometimes hard to know what to eat.

This can be particularly relevant as we grow older, and are trying to make the best choices to minimise the risk of health problems such as high blood pressure, obesity, type 2 diabetes, and heart (cardiovascular) problems.

We now have evidence these health problems also all affect brain function: they increase nerve degeneration in the brain, leading to a higher risk of Alzheimer’s disease and other brain conditions including vascular dementia and Parkinson’s disease.

We know a healthy diet can protect against conditions like type 2 diabetes, obesity and heart disease. Fortunately, evidence shows that what’s good for the body is generally also good for the brain.




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People living in rural areas may be at lower risk of Alzheimer’s disease


Oxidative stress

As we age, our metabolism becomes less efficient, and is less able to get rid of compounds generated from what’s called “oxidative stress”.

The body’s normal chemical reactions can sometimes cause chemical damage, or generate side-products known as free radicals – which in turn cause damage to other chemicals in the body.

To neutralise these free radicals, our bodies draw on protective mechanisms, in the form of antioxidants or specific proteins. But as we get older, these systems become less efficient. When your body can no longer neutralise the free radical damage, it’s under oxidative stress.

The toxic compounds generated by oxidative stress steadily build up, slowly damaging the brain and eventually leading to symptoms of Alzheimer’s disease.




Read more:
What causes Alzheimer’s disease? What we know, don’t know and suspect


To reduce your risk, you need to reduce oxidative stress and the long-term inflammation it can cause.

Increasing physical activity is important. But here we are focusing on diet, which is our major source of ANTIoxidants.

Foods to add

There are plenty of foods you can include in your diet that will positively influence brain health. These include fresh fruits, seafood, green leafy vegetables, pulses (including beans, lentils and peas), as well as nuts and healthy oils.

Fish

Fish is a good source of complete protein. Importantly, oily fish in particular is rich in omega-3 fatty acids.

Laboratory studies have shown omega-3 fatty acids protect against oxidative stress, and they’ve been found to be lacking in the brains of people with Alzheimer’s disease.

They are essential for memory, learning and cognitive processes, and improve the gut microbiota and function.

Oily fish, like salmon, is high in omega-3 fatty acids, which research shows can benefit our brain health.
From shutterstock.com

Low dietary intake of omega-3 fatty acids, meanwhile, is linked to faster cognitive decline, and the development of preclinical Alzheimer’s disease (changes in the brain that can be seen several years before for onset of symptoms such as memory loss).

Omega-3 fatty acids are generally lacking in western diets, and this has been linked to reduced brain cell health and function.

Fish also provides vitamin D. This is important because a lack of vitamin D has been linked to Alzheimer’s disease, Parkinson’s disease, and vascular dementia (a common form of dementia caused by reduced blood supply to the brain as a result of a series of small strokes).

Berries

Berries are especially high in the antioxidants vitamin C (strawberries), anthocyanins (blueberries, raspberries and blackberries) and resveratrol (blueberries).

In research conducted on mouse brain cells, anthocyanins have been associated with lower toxic Alzheimer’s disease-related protein changes, and reduced signs of oxidative stress and inflammation specifically related to brain cell (neuron) damage. Human studies have shown improvements in brain function and blood flow, and signs of reduced brain inflammation.




Read more:
Six things you can do to reduce your risk of dementia


Red and purple sweet potato

Longevity has been associated with a small number of traditional diets, and one of these is the diet of the Okinawan people of Japan. The starchy staple of their diet is the purple sweet potato – rich in anthocyanin antioxidants.

Studies in mice have shown this potato’s anthocyanins protect against the effects of obesity on blood sugar regulation and cognitive function, and can reduce obesity-induced brain inflammation.

Green vegetables and herbs

The traditional Mediterranean diet has also been studied for its links to longevity and lower risk of Alzheimer’s disease.

Green vegetables and herbs feature prominently in this diet. They are rich sources of antioxidants including vitamins A and C, folate, polyphenols such as apigenin, and the carotenoid xanthophylls (especially if raw). A carotenoid is an orange or red pigment commonly found in carrots.

Green vegetables and herbs provide us with several types of antioxidants.
From shutterstock.com

The antioxidants and anti-inflammatory chemicals in the vegetables are believed to be responsible for slowing Alzheimer’s pathology development, the build up of specific proteins which are toxic to brain cells.

Parsley is rich in apigenin, a powerful antioxidant. It readily crosses the barrier between the blood and the brain (unlike many drugs), where it reduces inflammation and oxidative stress, and helps brain tissue recovery after injury.




Read more:
What is the Mediterranean diet and why is it good for you?


Beetroot

Beetroot is a rich source of folate and polyphenol antioxidants, as well as copper and manganese. In particular, beetroot is rich in betalain pigments, which reduce oxidative stress and have anti-inflammatory properties.

Due to its nitrate content, beetroot can also boost the body’s nitric oxide levels. Nitric oxide relaxes blood vessels resulting in lowered blood pressure, a benefit which has been associated with drinking beetroot juice.

A recent review of clinical studies in older adults also indicated clear benefits of nitrate-rich beetroot juice on the health of our hearts and blood vessels.

Foods to reduce

Equally as important as adding good sources of antioxidants to your diet is minimising foods that are unhealthy: some foods contain damaged fats and proteins, which are major sources of oxidative stress and inflammation.

A high intake of “junk foods” including sweets, soft drinks, refined carbohydrates, processed meats and deep fried foods has been linked to obesity, type 2 diabetes and cardiovascular disease.

Where these conditions are are all risk factors for cognitive decline and Alzheimer’s disease, they should be kept to a minimum to reduce health risks and improve longevity.




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Health check: can eating certain foods make you smarter?


The Conversation


Ralph Martins, Professor, Department of Biomedical Sciences, Macquarie University

This article is republished from The Conversation under a Creative Commons license. Read the original article.