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Published on: May 7, 2019
by Women’s Brain health Initiative:
There are two categories of genes that influence whether an individual will develop Alzheimer’s disease (AD): risk genes and deterministic genes. Risk genes increase the likelihood of developing the disease, but do not guarantee that it will happen. Apolipoprotein E (APOE) is the gene most commonly associated with late-onset AD, and it has three variants (or alleles):
Deterministic genes, on the other hand, directly cause the disease, guaranteeing that anyone who inherits this type of gene will develop early-onset AD. Scientists have identified three rare deterministic genes that will result in AD: amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). However, these genes are estimated to account for less than 1% of all cases of AD.
Aside from genetics, then, what else might be influencing who develops AD and who does not?
Scientists believe that complex interactions between genetic and environmental factors are at play, and that epigenetics may be the underlying mechanism affecting those interactions. Epigenetics is an emerging field in science that studies the “additional layer of information” that controls when and where genes are expressed, without changing the DNA sequence.
What is particularly interesting is that while genes are fixed, gene expression (i.e. how a gene ultimately functions) is not. Instead, some epigenetic marks can change over time in response to external stressors and lifestyle choices.
Outside factors that are known to impact health such as exercise, diet, and exposure to chemicals have been shown to affect the epigenome.
Neuroepigenetics is the term used to describe epigenetic changes specifically in the brain. To date, this field of study has provided insights into brain and mental health issues such as addiction, depression, post-traumatic stress disorder, and AD.
The investigation of how epigenetic marks impact genes in AD is a fairly new area of study, and there is still a tremendous amount to learn. Research to date has shown that epigenetic mechanisms are dysregulated during the progression of AD, starting early in the disease process. It is not clear, though, if the epigenetic changes that have been observed are a cause or consequence of AD.
One recent study conducted by a team of researchers from the Perelman School of Medicine at the University of Pennsylvania, published in Nature Neuroscience in April 2018, examined the epigenetic landscape in post-mortem brain tissue donated by individuals with AD, as well as younger and elderly cognitively-normal control subjects. The researchers discovered epigenetic differences between the AD brains and healthy-aging brains. In particular, they found differences in an epigenetic mechanism referred to as acetylation of lysine 16 on histone H4 (H4K16ac).
“H4K16ac is a key factor in human health because it regulates responses to stress and DNA damage,” explained Dr. Shelley Berger, a professor at the Perelman School of Medicine and one of the study’s authors. “In this study, we found that normal aging leads to increases in H4K16ac – in new positions along the genome, as well as in locations where it is already present. In contrast, AD brains showed losses of H4K16ac in locations close to certain genes that have been linked to aging in Alzheimer’s disease.”
This finding suggests that during the healthy aging process, epigenetic changes occur in the brain that may protect against AD, but when these go awry, a person may become predisposed to developing the disease.
Alzheimer’s is a disease known to develop over a long period of time, with symptoms only becoming evident late in the process. Epigenetic alterations might be occurring early in the disease process, though, making them a potential biomarker that could aid in diagnosis and a possible target for new therapies.
“Our study findings do not suggest a cure for Alzheimer’s disease,” emphasized Dr. Berger. “However, they do suggest that H4K16ac could represent a potential target for future drug development aimed at preventing AD progression early on.”
Recently, a group of researchers from Drexel University in the U.S. conducted a study on fruit flies and successfully reversed symptoms of AD by restoring the balance between two epigenetic enzymes that regulate gene expression. The research focused on the balance between histone deacetylase 2 (HDAC2) – an enzyme known to help control the expression of genes linked to memory and learning – and Tip60 histone acetyltransferase (Tip60 HAT). It appears that when HDAC2 is more abundant than Tip60 HAT, gene expression is repressed, which leads to problems with neuroplasticity (the brain’s ability to adapt to new stimuli or recall reactions to stimuli that it has already encountered).
The researchers discovered that if they added extra Tip60 HAT to the brains of flies with Alzheimer’s-like symptoms, the balance between the two enzymes could be successfully restored. Moreover, when that balance was reinstated, the flies were able to re-learn and remember behaviours that the researchers previously taught the flies. These findings were published in The Journal of Neuroscience in May 2018.
“By studying fruit flies during an early stage of their development, our research team was able to look at what happens early in the neurodegeneration process,” said Dr. Felice Elefant, associate professor at Drexel University and one of the authors of the study. “As a result, we were able to test an intervention aimed at correcting what is happening during those early stages. Our positive results warrant further research related to Tip60 HAT activators as a potential Alzheimer’s treatment.”
H4K16ac and the HDAC2/Tip60 HAT enzymes are not the only epigenetic mechanisms that have been found to have an association with Alzheimer’s disease. They represent just two examples of potential epigenetic targets for treatment that have been discovered to date.
Research involving the study of neuroepigenetic mechanisms is an enormous undertaking. The mapping of genes (i.e. the human genome) has been extremely complex and it is just the basic infrastructure upon which epigenetic mechanisms operate. The study of epigenetics is so challenging because of the vast number of potential combinations of epigenetic marker type and location.
While this research continues, there is much that we can do to apply what is already known about epigenetics.
An individual’s epigenetic landscape changes over time in response to external influences, some of which we have control over.
There is an abundance of research that points to the benefits of making healthy lifestyle choices for your brain (e.g., engaging in physical and mental exercise, staying socially engaged, consuming healthy foods, sleeping well, meditating, and participating in other activities for stress relief). Knowing that the decisions we make affect the epigenetic marks in our brains (and correspondingly influence our brain health) is a powerful motivator to start making brain-healthy choices today.
Source: MIND OVER MATTER V8
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