New link found between Alzheimer's disease and healthy ageing
Researchers have analyzed changes in gene expression in ageing and diseased brains, finding new clues to the biology of normal ageing and neurodegenerative diseases. The research, published in Genome Research, was conducted by an international team of scientists. Co-authors from the Institute of Psychiatry (IOP) at King’s College London include Dr Boris Rogelj, Dr Tibor Hortobágyi and Prof Chris Shaw head of the MRC Centre for Neurodegeneration Research.
Alzheimer's disease and frontotemporal lobar degeneration (FTLD) are two of the most prevalent forms of neurodegenerative disorders. Overall, FTLD occurs less frequently than Alzheimer’s disease, and is relatively uncommon in individuals over the age of 65. However, it is significant in younger people (those under 65) and is the second most common neurodegenerative disorder in this age group.
Previous studies have identified changes in how genes are read, or expressed, in the brain either during ageing or with neurodegenerative disease. However, no previous study had directly compared gene expression changes in healthy ageing with those in diseased individuals.
In this report, researchers analyzed and compared changes in gene expression associated with ageing and disease in a region of the brain known to be affected in both Alzheimer's and FTLD.
Prof Shaw says: ‘Using post-mortem brain samples obtained from the IOP’s MRC London Neurodegenerative Diseases Brain Bank
, we have compared gene expression and alternative splicing changes in healthy individuals ranging from 16 to 102 years old with individuals who died of Alzheimer’s disease or FTLD. We uncovered striking similarity in the changes in gene expression patterns associated with ageing and the neurodegenerative diseases.’
The researchers observed that the diseased samples displayed the same age-related changes as healthy individuals over the age of 80.
Dr Rogelj says: ‘The majority of the diseased individuals were younger than 70 and some were even in their 50s. Even at this relatively young age, ageing-related changes were still apparent. This is roughly 25 years before we would expect to see similar changes in healthy individuals.’
While the similarities were striking, the group also observed notable differences between gene expression in the normal ageing brain and expression in Alzheimer's and FTLD. The differences were particularly apparent in the patterns of alternative splicing, a process by which parts of an RNA molecule are arranged differently to change the message. Changes at this level can be potentially harmful if misregulated.
In normal ageing, changes in alternative splicing largely affected genes associated with cellular metabolism, while disease-specific changes were associated with genes involved in neuron-specific function. The group found that there were changes in the expression of several genes coding for RNA binding proteins, which is likely responsible for at least part of the observed alterations in splicing.
The authors expect that this work will have broad impact for further insight into both normal ageing and neurodegenerative disease.
Dr Rogelj adds: ‘Studying the process behind healthy ageing could help us better understand the processes that lead to neurodegeneration. Conversely, our findings also indicate that studies of neurodegenerative diseases might help us understand how to delay the changes that take place in healthy individuals at an advanced age.’
Scientists from the MRC Laboratory of Molecular Biology (Cambridge, UK), the MRC Centre for Neurodegeneration Research (London, UK), the EMBL-European Bioinformatics Institute (Hinxton, UK), Affymetrix, Inc. (Santa Clara, CA), and the University of Ljubljana (Ljubljana, Slovenia) contributed to this study.
This work was supported by the European Research Council, the Medical Research Council, the Slovenian Research Agency, and a Wellcome Trust and Medical Research Council Strategic Grant Award.
Tollervey, JR. et al. ‘Analysis of alternative splicing associated with ageing and neurodegeneration in the human brain’, Genome Research
(2011) doi: 10.1101/gr.122226.111
Image: The image shows a vertical slice through the brain of an individual having suffered from Alzheimer’s disease on the left, compared to a healthy brain on the right. The Alzheimer’s disease brain is considerably shrunken due to the degeneration and death of nerve cells.
For more information, please contact Seil Collins, IOP Press Officer