Neurons Changing their DNA Could Lead to Alzheimer’s Disease

A recent study finds that neurons can spontaneously change the sequence of a gene called APP, which is involved with Alzheimer’s disease.

In most cases, the DNA that you’re born with stays the same throughout your entire life. However, according to a paper recently published in Nature, neurons can randomly change their own DNA sequence, which may contribute to the development of Alzheimer’s disease.

The study was led by Dr. Jerold Chun’s research group at the University of California San Diego and the Sanford Burnham Prebys Medical Research Institute. Dr. Chun’s lab and others have previously shown that adult neurons can alter their own DNA sequence. As a result, different neurons inside your brain can have their own unique genomes, a phenomenon known as genomic mosaicism. This is distinct from epigenetic modifications, which can turn genes on or off but do not change the actual genetic sequence.

Genomic mosaicism, which occurs by a seemingly random process, can range in size from a single nucleotide to entire chromosomes. These changes tend to accumulate as we age, which led many scientists to wonder if they could be related to neurodegenerative diseases.

Our Mosaic Brains and Alzheimer’s Disease

In their recent Nature paper, Dr. Chun’s group investigated a single gene called Amyloid Precursor Protein, or APP for short. APP is the precursor to amyloid-beta, a toxic sticky protein that builds up in the brains of people with Alzheimer’s disease. The researchers were curious whether different forms of the APP gene could exist throughout the brain.

Using postmortem brain samples from five people with sporadic Alzheimer’s disease, as well as five age-matched controls, they extracted DNA from individual neurons and sequenced the APP gene. They found that more than 6,000 variants of APP existed across different neurons.

Interestingly, the Alzheimer’s brains had far greater diversity of genetic variants than the healthy brains. This suggests that these unusual APP variants could be related to the development of Alzheimer’s. When they took three of these variants and expressed them in a cell culture, two of them resulted in cell death. In addition, the Alzheimer’s brains had several APP variants that have been linked to familial Alzheimer’s disease (a rare, genetic form of early-onset Alzheimer’s), while none of the healthy brains contained these variants.

Next, the researchers wanted to understand how all these different APP variants might arise in neurons. They used a hamster cell culture that was made to express the human APP gene. When they used chemicals to induce DNA double-stranded breaks, the cells began producing unique APP variants, just like human neurons. The researchers also showed that this process relies on reverse transcription, which converts an RNA sequence to DNA.

Impacts for Alzheimer’s, AIDS, and Memory

This discovery is a major shift for Alzheimer’s researchers. Previous anti-APP drug candidates have generally only targeted one form of the gene, and this work shows that a huge array of genetic variants can exist in our brains. We will certainly need to reconsider our strategy for Alzheimer’s therapies moving forward.

In addition, the link between genomic mosaicism and reverse transcription has some intriguing implications for HIV. Previously studies have shown that people with HIV who are over age 65 have a lower rate of Alzheimer’s disease than the general population. One explanation could be the anti-retroviral drugs that they take. These drugs prevent the HIV multiplying by inhibiting reverse transcription, a process that the virus requires for replication. An unintended consequence of this could be that these people do not develop the APP variants that are linked to Alzheimer’s. If this turns out to be the case, anti-retroviral drugs could possibly be used as a preventative measure for Alzheimer’s.

So far, none of this has addressed the reason why neurons are so prone to developing different APP variants. In the Nature study, another Alzheimer’s-related gene called PSEN1 did not have such a wide variety, suggesting that the mechanism is specific to APP. In addition, non-neuronal cells did not develop all these APP variants. A possible explanation could be that this process is important for memory formation. The authors suggest that storing so many unique version of APP could be a mechanism for memory storage and recall at the molecular level. This idea remains speculative, but it does have a kind of poetic irony to it: the gene responsible for forming memories could also destroy those memories as we age.

 

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Interview with a Dementia Researcher: Rory Boyle, Cognitive Neuroscience Researcher

What areas of research are you currently pursuing?

My PhD research is focused on using machine learning to identify markers of cognitive ageing. Currently, I am working on a project which uses machine learning and MRI scans to create a model of normal or healthy brain ageing. This model can be used to estimate how well, or poorly, a person’s brain is ageing and this estimation is termed the brain-predicted age difference, or brainPAD.

It has already been shown that people who have high brainPAD scores (which means their brains are ‘older’ relative to their actual age) have a higher risk of early mortality and tend to perform worse on measures of physical functioning (such as grip strength, lung function, walking speed).

However, we don’t yet know whether brainPAD can be used as a measure of cognitive ageing. If people with high brainPAD scores are shown to perform worse on tests of cognitive function, then brainPAD could potentially be used as a way of identifying such people at a very early stage, before cognitive decline is noticed using standard cognitive tests.

The next project in my PhD will look at developing an objective measure of cognitive reserve. Some people whose brains have the hallmarks of Alzheimer’s disease or other dementias seem to be able to maintain normal cognitive function. This has led researchers to try and understand why some people might have a buffer or some form of protection against certain neurodegenerative diseases. One theory is that people who are able to tolerate such neurodegeneration have high levels of what is called ‘cognitive reserve’.

Cognitive reserve refers to an individual’s ability to use their brain irrespective of their brains’ structural health. It is proposed that life experiences, such as education, occupational attainment, engagement in social, leisure, and mentally stimulating activities, and physical activity contribute to cognitive reserve.

However, currently, cognitive reserve is typically measured by questionnaires and interviews which measure these same factors (education, occupational attainment, etc.). This means that we might not have the most accurate measures, as people might not fully remember all the details of their education or social activities and their answers might be affected by response bias!

My goal is to use neuroimaging to develop an objective and standardised measure of cognitive reserve so that people with low cognitive reserve can be identified. This would allow for interventions to be directed at these people and it would also help in studies evaluating strategies to improve cognitive reserve.

What are the big questions or theories currently being debated in your subfield?

There are a couple of big questions which people are trying to answer in relation to cognitive reserve. Can cognitive reserve be objectively measured, and if so, how? What is the neural basis of cognitive reserve? Hopefully my project will help to shed some light on these questions.

What is a common misconception related to dementia that you often encounter?

One common misconception is that there nothing we can do to reduce our risk of dementia. Given our knowledge of cognitive reserve, one way we could reduce our risk of dementia is by increasing cognitive reserve! There is more and more evidence that taking part in mentally stimulating activities, being socially active, and regularly exercising can lower the risk of dementia. More generally, there is evidence that having a healthy diet, particularly a Mediterranean diet, not smoking, and cutting down on alcohol can also reduce the risk of dementia.

What recommendations would you give to people wanting to reduce their risk of Alzheimer’s disease?

Like a lot of things, the best recommendations for reducing risk of Alzheimer’s disease or other dementias are to live a healthy and active life. Specifically, try to exercise three times a week, particularly aerobic exercise like brisk walking, swimming, cycling. As well as that, try to stick to a Mediterranean diet, which is rich in fruits and vegetables, whole grains, beans and nuts, olive oil and fish.

Be socially active, join a group or club. In Ireland, we have a really great initiative called Men’s Sheds were men can meet up and work together on hobbies and meaningful projects. This is a great example of how people can keep socially engaged. As well as that, take part in mentally stimulating activities like puzzles and Sudoku. If you have access to a PC, there are now thousands of free online courses on websites like Coursera or EdX. By signing up for these, you can challenge yourself and learn something new, all while keeping your brain stimulated!

How can non-scientists contribute to the fight against Alzheimer’s?

Non-scientists could help in the fight against Alzheimer’s by taking part in research. Research studies are always on the lookout for participants. People without Alzheimer’s disease are always needed as well to form control groups. Have a look online or at any nearby universities!

On top of that, there are now even easier ways to take part in research. For example, downloading and playing the SeaHero Quest app allows researchers to collect valuable information about how the brain navigates in space, which is a key skill that declines early on in dementia.

When do you believe a viable Alzheimer’s treatment will be available?

I’m not sure, but I am hopeful that with all of the new techniques we will be able to identify people likely to develop Alzheimer’s or other dementias, earlier than ever before. This will allow for any interventions that can help with Alzheimer’s to be implemented at the early stages of the disease, where interventions are likely to be most specific. It will also help researchers test and monitor the effects of new interventions and treatments.

Is there any other information you’d like to add?

My PhD research is funded by the Irish Research Council, in partnership with Altoida AG. I am very grateful for the support of both of these organisations. Altoida AG has developed an app that uses computerised and gamefied tests of cognitive performance to evaluate perceptual and memory function in older adults. This app may ultimately allow for early screening of mild cognitive impairment and identification of people who are at risk of developing Alzheimer’s disease. We have tested this app on a number of older adults here in Trinity College, and hopefully we will have some interesting data from these tests in the next year!

 

Rory Boyle is a PhD candidate in the Whelan Lab in Trinity College Dublin. He graduated with a BSc in Psychology from Dublin City University in 2014, and an MSc in Brain Sciences from the University of Glasgow in 2016. His BSc research project compared the effects of aerobic exercise and caffeine consumption on measures of mood and cognitive performance. His MSc research project used EEG to investigate the age-related differences in the visual processing of faces. Specifically, his project examined whether there were differences in the information content of brain activity during the visual processing of faces.

 

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