From the analysis of the brains of people who died with Alzheimer’s, researchers have identified the possible underlying cause of the disease, a discovery that could lead to innovative therapeutic approaches against neurodegeneration.
To date, the underlying causes of the disease are not yet fully known Alzheimer’s diseasethe main form of dementia in the world. Several are known risk factors important, like old agegenetic mutations, lifestyle and physical conditions. Being a woman also carries a higher risk, approximately double that of men. Nonetheless, full light has not yet been shed on the processes that determine the neurodegenerationthe death of neurons that results in cognitive decline, characterized by memory loss, difficulty orienting, speech problems, and other conditions. A new, pioneering study, however, may have discovered one of the most important mechanisms linked to the development of illness and, with it, the hope of new therapeutic approaches. Alzheimer’s, we remember, is currently incurable.
The authors of the new research observed that in brain of people who died with Alzheimer’s there is a higher percentage of cells with signs of agingfurthermore, a reduced interaction between the DNA strongly folded (chromatin) andRNA. In other words, brain cells – like i neurons they oligodendrocytes – they can age uniformly, with some doing so more rapidly and others less; Alzheimer’s could be triggered by this rapid agingwhich in turn can compromise the ability of interaction between deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), with the latter responsible for the transcription of the information contained in the former.
An international research team led by scientists from the University’s Program in Bioinformatics and Systems Biology determined that the brains of people with Alzheimer’s have a higher percentage of older brain cells and that their DNA interacts less with RNA. University of California San Diego, who collaborated closely with colleagues in the Department of Bioengineering and Shu Chien-Gene Lay and the Institute of Engineering in Medicine. The researchers, coordinated by Professor Sheng Zhong, reached their conclusions after thoroughly analyzing the brain of 14 deceased donorsfocusing in particular on frontal cortex. The minimum age was 59 and some had died with dementia, others had not. To conduct the analyses, the researchers used a pioneering method called MUSIC, an acronym for multinucleic acid interaction mapping in individual cells. It’s so powerful that it has a single cell resolution and even be able to observe chromatin interactions between DNA and RNA.
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The researchers explain that over time these interactions, linked to fundamental biological processes, change significantly. Thanks to MUSIC, the authors of the new study discovered that in the brains of Alzheimer’s patients these “exchanges” are particularly reduced. Furthermore, as indicated, it was observed that in people who died with Alzheimer’s there were many more cells with signs of aging. In a further experiment on mouse models it was found that in females there is a higher ratio of oligodendrocytes (supporting brain cells) and aged neurons compared to males; this may explain why women have a higher risk of dementia than men.
“With this transformative single-cell technology, we discovered that some brain cells are ‘older’ than others. If we could identify dysregulated genes in these aged cells and understand their functions in local chromatin structure, we could also identify new potential therapeutic targets,” said Professor Zhong. The details of the research “Single-cell multiplex chromatin and RNA interactions in aging human brain” were published in the prestigious scientific journal Nature.
