20 Apr Neurons in Alzheimer’s Disease Have Different Mutations Than Those That Occur in Normal Aging
MedicalResearch.com Interview with:
Michael B. Miller, MD, PhD
Instructor, Harvard Medical School
Department of Pathology
Brigham and Women’s Hospital
MedicalResearch.com: What is the background for this study? Would you explain what is meant by somatic genetic changes and how they might occur?
Response: Changes, also called mutations, in the DNA sequence of genes can be passed from parents to their children, and explain why many diseases run in families. This kind of DNA change is called a germline mutation and is present in every cell in a person’s body. Gene mutations can also occur in a subset of cells of a person, in which case they are called somatic mutations. Somatic mutations are well known as a cause of cancer, and recent research has found that somatic mutations can also happen in non-cancerous cells that appear otherwise normal. Recent studies have even found that somatic mutations are present in neurons, cells in the brain that transmit electrical signals and play an important role in how the brain functions. Furthermore, in neurons, somatic mutations increase with age, so we set out to understand if somatic mutations might be playing a role in age-related brain diseases like Alzheimer’s.
MedicalResearch.com: What are the main findings?
Response: We used a method called single-cell whole-genome sequencing, which determines the sequence of the DNA inside individual cells, and studied neurons from Alzheimer’s disease (AD) and from people of similar ages who did not have Alzheimer’s disease. We found that neurons in AD have more somatic mutations, specifically a type called somatic single-nucleotide variants (sSNV), than the neurons of people without AD. We found that the “extra” mutations in AD are different than the mutations that happen during normal aging — the specific changes in the DNA base letter are different, including many C-to-A changes in Alzheimer’s disease. We also found that AD neurons have more oxidative damage, which we think is responsible for some of the C-to-A changes.
MedicalResearch.com: What should readers take away from your report?
Response: The genome of brain cells in Alzheimer’s disease seems to be fundamentally different than the genome of normal cells. These genomic differences may impact why brain cells are more likely to die in Alzheimer’s disease. Also, the presence of these somatic mutation genomic changes in brain cells gives us an opportunity to better understand what happens in those cells during disease, which we may be able to use to identify new ways to diagnose and treat disease.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Finding these differences in a cell’s genome in Alzheimer’s disease has opened our eyes to the genomic changes in neurodegeneration. This provides an opportunity to examine the causes of these changes to better understand the factors that actually cause Alzheimer’s disease. We are also interested to test if similar genomic damage occurs in other neurodegenerative diseases.
MedicalResearch.com: Is there anything else you would like to add?
Response: While I had the opportunity to lead this study with my collaborator August Huang, under the mentorship of Christopher Walsh, Alice Lee, and Michael Lodato, this research was the result of a broad collaboration of researchers at Brigham and Women’s Hospital, Boston Children’s Hospital, Massachusetts General Hospital, and many others.
Disclosures and funding are included in the Brigham press release.
Miller, M.B., Huang, A.Y., Kim, J. et al. Somatic genomic changes in single Alzheimer’s disease neurons. Nature (2022). https://doi.org/10.1038/s41586-022-04640-1
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