Public Release: 

Losing control of gene activity in Alzheimer's disease

University of Exeter

Pioneering research into the mechanisms controlling gene activity in the brain could hold the key to understanding Alzheimer's disease and might help identify effective treatments in the future.

An international research team led by scientists at the University of Exeter and the University of Essex have uncovered a link between indicators of gene activity and the disease, which could unlock exciting new avenues of research.

The study is published in Nature Neuroscience and was co-funded by the United States National Institutes of Health, the European Union and the Medical Research Council.

The group investigated changes to the activity of genes which are not caused by variation in the actual genetic code. It is an exciting avenue for research because unlike the DNA sequence, these so-called epigenetic processes can potentially be altered by environmental factors, providing a possible future avenue to influencing their activity.

The researchers studied a type of epigenetic modification called histone acetylation that marks regions of the genome that are active. In cells, DNA is packaged by structures called histones which can be modified to control gene activity. The team quantified levels of histone acetylation across the genome using brain tissue from deceased patients with and without Alzheimer's disease.

Both increases and decreases in histone acetylation were found across regions of the genome, identifying genes involved in Alzheimer's disease. Strikingly, they found differences in regulatory regions controlling the expression of both amyloid and tau, two proteins known to be involved in the pathology of Alzheimer's disease.

This research is the first genome-wide study to investigate histone acetylation in Alzheimer's disease, and provides a framework for studying histone modification studies in other diseases affecting the brain.

Professor Jonathan Mill, who co-led the study, of the University of Exeter Medical School said: "Our study provides compelling evidence for widespread changes in histone acetylation in Alzheimer's disease. Although more work is needed to explore whether altered histone acetylation is a cause or a result of the condition, it is interesting that drugs modifying histone acetylation are among the most promising new treatments for Alzheimer's disease."

Fellow co-lead Professor Leonard Schalkwyk, from the School of Biological Sciences at the University of Essex, said: "Alzheimer's affects millions of lives and has been extensively studied but we still haven't got to the bottom of why and how it happens. This is our second large-scale study on the chromosomes of the most-affected parts of the brain, to find different epigenetic differences in how genes are expressed in Alzheimer's disease compared to an unaffected brain. This is helping to tie different strands of our understanding of the disease together."

Dr Sarah Marzi, from King's College London and Queen Mary University of London, who was part of the research team added: "Changes influencing the activity of many genes were found to be robustly associated with the pathological hallmarks of Alzheimer's disease. Interestingly, our results suggest there are common mechanisms both hereditary and isolated forms of this terrible illness."

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Alzheimer's disease is the leading cause of dementia, which effects 850,000 people in the UK alone. This is set to rise to over 1 million people by 2025.

The paper, A histone acetylome-wide association study of Alzheimer's disease: neuropathology-associated regulatory variation in the human entorhinal cortex, is published in Nature Neuroscience. The full list of authors is as follows: Sarah J. Marzi, Szi Kay Leung, Teodora Ribarska, Eilis Hannon, Adam R. Smith, Ehsan Pishva, Jeremie Poschmann, Karen Moore, Claire Troakes, Safa Al-Sarraj, Stephan Beck, Stuart Newman, Katie Lunnon, Leonard C. Schalkwyk, Jonathan Mill.

About the University of Exeter Medical School

The University of Exeter Medical School is improving the health of the South West and beyond, through the development of high-quality graduates and world-leading research that has international impact.

As part of a Russell Group university, we combine this world-class research with very high levels of student satisfaction. The University of Exeter Medical School's Medicine programme is ranked 5th in the Guardian Guide 2018, while Medical Imaging is ranked 2nd, in the Complete University Guide 2018, under Radiography. Exeter has over 19,000 students and is ranked 14th in The Times and The Sunday Times Good University Guide 2018. In the 2014 Research Excellence Framework (REF), the University ranked 16th nationally, with 98% of its research rated as being of international quality. Exeter's Clinical Medicine research was ranked 3rd in the country, based on research outputs that were rated world-leading. Public Health, Health Services and Primary Care research also ranked in the top ten, in joint 9th for research outputs rated world-leading or internationally excellent.

https://medicine.exeter.ac.uk/

About the University of Essex

The University of Essex is ranked in the top 30 of The Times and Sunday Times Good University Guide 2019 and we're shortlisted for University of the Year in the Times Higher Education Awards. We're also ranked 25th for research quality (TGUG 2019) and we were awarded the top gold rating in the Government's Teaching Excellence Framework in 2017. The 2018 National Student Survey results placed Essex top 15 for the sixth year for overall student satisfaction (English mainstream universities*).

Confirming our global reputation, the Times Higher Education World University Rankings 2019 placed Essex in the top 300 in the world and 14th for international outlook while the QS World University Rankings ranked us 25th for the most international student community. We're ranked in the top 50 for social sciences in the Times Higher Education World University Rankings by Subject and ranked top 50 for politics and sociology in the QS World University Rankings by Subject.

http://www.essex.ac.uk

About Queen Mary University of London

Queen Mary University of London is a world-leading research-intensive university with over 25,000 students representing more than 160 nationalities.

A member of the prestigious Russell Group, we work across the humanities and social sciences, medicine and dentistry, and science and engineering, with inspirational teaching directly informed by our research.

In the most recent exercise that rated research in the UK, we were ranked 5th in the country for the proportion of research outputs that were world-leading or internationally excellent. We offer more than 240 degree programmes and our reputation for excellent teaching was rewarded with a silver in the 2017 Teaching Excellence Framework (TEF) awards.

Queen Mary's history dates back to 1785, with the foundation of the London Hospital Medical College. Our history also encompasses the establishment of the People's Palace in 1887, which brought accessible education, culture and recreation to the East End of London. We also have roots in Westfield College, one of the first colleges to provide higher education to women.

About King's College London

King's College London is one of the top 25 universities in the world (2017/18 QS World University Rankings) and among the oldest in England. King's has more than 26,500 students (of whom nearly 10,400 are graduate students) from some 150 countries worldwide, and nearly 6,900 staff. The university is in the second phase of a £1 billion redevelopment programme which is transforming its estate. http://www.kcl.ac.uk

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