Cells throughout the body naturally accumulate DNA mutations as we age. With Alzheimer’s disease, mutations occur in brain cells at a much faster rate than normal. Thanks to a recent study researchers from Brigham Women’s Hospital and Boston Children’s Hospital, we may be one step closer to understanding why this is happening.
Whole-genome sequencing of more than 300 brain cells revealed significant oxidative DNA damage in the hippocampus and prefrontal cortex, two of the main regions affected by Alzheimer’s disease. Generalized mutations in the genome appear to be linked to increased exposure to reactive oxidant species, produced in response to tau and amyloid-β protein accumulation in Alzheimer’s disease. This study by Miller et al. not only sheds light on the underlying mechanisms of Alzheimer’s disease, but also the natural consequences of aging.
Oxidative DNA damage comes in different forms from external and internal sources. Even normal cellular metabolic processes can produce byproducts of superoxide, a molecule known to be a precursor to other reactive oxygen species. At low levels, reactive oxygen species have been shown to play a role in cell signaling and the maintenance of homeostasis. Allowing these molecules to build up in a cell, however, can disrupt cellular function, not to mention destabilize DNA. Although cells have evolved ways to minimize the impact of reactive oxygen species, these mechanisms are not perfect. Repairing regions of DNA with oxidative damage may also pose the risk of further destabilizing the genome and producing more mutations. When a region of DNA suffers oxidative damage, the cell must make a difficult decision between repairing the damage or leaving it unrepaired.
DNA mutations are transmitted each time a cell is regenerated and therefore accumulate over time. Studies suggest that these mutations not only contribute to the aging process, but also to the development of certain age-related diseases. Alzheimer’s disease, for example, is associated with significant oxidative stress marked by increased production of reactive oxygen species and oxidative damage to both DNA and RNA. To determine the extent of this damage, this study is the first to sequence the entire genome of individual neurons located in the prefrontal cortex and hippocampus from postmortem brain samples from people with and without the disease. Alzheimer’s.
Compared to neurotypical adults, the first survey by Miller et al. revealed many more DNA mutations in people diagnosed with Alzheimer’s disease. As Dr. Michael B Miller, lead author and Brigham Professor of Pathology, said, “These results suggest that AD neurons are experiencing genomic damage that places immense stress on cells and creates dysfunction between them. findings may explain why many brain cells die during AD.
DNA mutations can have important consequences on the transcription, as well as on the expression, of genes. Transcription of a modified nucleotide can prevent the correct amino acid from being attached to a protein sequence and completely alter the function of the protein. As these mutations accumulate over time, an entire gene can cease to be expressed permanently. In fact, the researchers found a higher prevalence of dysfunctional neurons with important genes that were no longer expressed in people with Alzheimer’s disease compared to the neurotypical control group.
The DNA damage seen in people diagnosed with Alzheimer’s disease exceeded the pattern of damage associated with normal age-related mutations. Furthermore, a greater proportion of mutations among this group more often impacted genes important for neuronal function, as well as survival. The researchers concluded that there are likely several mechanisms contributing to the increase in DNA mutations that may be specific to Alzheimer’s disease.
Although there was evidence for an increase in age-related DNA changes, most of the damage observed by investigators appeared to be the result of oxidative damage to nucleotides. In particular, DNA mutations commonly affect guanine nucleotides. When exposed to reactive oxygen species, these nucleotides can mutate into 8-oxoguanine. Since the prevalence of this altered nucleotide is often used as a biomarker of oxidative DNA damage, the researchers were surprised to find significantly elevated levels of 8-oxoguanine in the DNA of neurons from people with the disease. alzheimers,
How did these cells acquire so much oxidative damage? Several factors likely contributed to these mutations. One of the leading theories suggests that increased brain inflammation during Alzheimer’s disease exposes brain cells to high levels of reactive oxygen species. In addition to the accumulation of neurofibrillary -β and tau proteins, repeated activation of the brain’s main immune defense mechanism, microglia, has been shown to correlate with cognitive decline in Alzheimer’s disease. The presence of amyloid-β proteins would induce microglia to release not only cytokines but also reactive oxygen species in an effort to clear the extracellular space. As the disease progresses and proteins continue to accumulate, the microglial cells continually produce cytokines and reactive oxygen species, which consequently damages the cells.
There remains a major piece of the puzzle: what causes the buildup of amyloid-β and tau? Previous studies have shown that amyloid-β plaques can build up in the brain for up to 10 years before you experience any symptoms. Yet there are several critical aspects of Alzheimer’s disease that we still do not understand, including the mechanism by which the presence of amyloid-β and tau proteins induce inflammation and oxidative stress. The results of this study bring us one step closer to uncovering these mysteries.
More than six million Americans currently have Alzheimer’s disease, although current projections warn that this neurodegenerative disease will become increasingly common as the general population ages and lives longer. Even if we cannot prevent the accumulation of amyloid-β and tau proteins, we may at least be able to develop treatments that reduce the level of oxidative damage in the brain and extend the life expectancy of people diagnosed with it. this and others. neurodegenerative disorders.
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