Study reveals a new way to think about Alzheimer’s disease

Cells throughout the body naturally accumulate DNA mutations as we age. In Alzheimer’s disease, mutations in brain cells occur much faster than normal. thanks to a recent research from researchers at 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 primary regions of Alzheimer’s disease. Widespread mutations in the genome appear to be associated with increased exposure to reactive oxidative species produced in response to the accumulation of tau and amyloid-β proteins during Alzheimer’s disease. This study by Miller et al. sheds light not only on the underlying mechanisms of Alzheimer’s disease, but also on the natural consequences of aging.

Oxidative DNA damage comes in various forms from both 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 maintenance of homeostasis. However, if these molecules build up in a cell, it can disrupt cellular function, not to mention destabilize DNA. While cells have developed ways to minimize the impact of reactive oxygen species, these mechanisms are not perfect. Repairing regions of DNA with oxidative damage can also carry the risk of further destabilizing the genome and producing more mutations. When a region of DNA undergoes oxidative damage, the cell must make a delicate decision to repair the damage or leave it unrepaired.

Every time a cell is regenerated, DNA mutations are passed on, causing them to accumulate over time. Studies suggest that such mutations contribute not only to the aging process, but also to the development of certain age-related diseases. For example, Alzheimer’s disease is associated with extensive oxidative stress characterized by the increased production of reactive oxygen species and oxidative damage to both DNA and RNA. To determine the extent of such damage, this study is the first to sequence the entire genome of individual neurons in the prefrontal cortex and hippocampus from the postmortem brain samples of people with and without Alzheimer’s disease.

Compared to neurotypical adults, the first study by Miller et al. revealed significantly more DNA mutations in those diagnosed with Alzheimer’s disease. Like dr. Michael B Miller, lead author and Professor of Pathology at Brigham, said: “These results suggest that AD neurons experience genomic damage that puts enormous stress on cells and causes dysfunction between them. These findings may explain why many brain cells die during AD.”

DNA mutations can have significant effects on both the transcription and expression of genes. Transcription of an altered nucleotide can prevent the correct amino acid from being attached to a protein sequence and completely change the function of the protein. As these mutations accumulate over time, an entire gene cannot be expressed permanently. In fact, researchers found a greater prevalence of dysfunctional neurons with key genes that were no longer expressed in people with Alzheimer’s disease compared to the neurotypic control group.

The DNA damage seen in individuals diagnosed with Alzheimer’s went beyond the pattern of damage associated with normal age-related mutations. Also, a higher proportion of mutations in this group more often affected genes important for neuron function and survival. Researchers concluded that there are likely several mechanisms that contribute to increased DNA mutations that may be specific to Alzheimer’s disease.

While there was some evidence of increased age-related DNA changes, most of the damage researchers observed appeared to be due to oxidative damage to nucleotides. In particular, DNA mutations often affect guanine nucleotides. When exposed to reactive oxygen species, these nucleotides can mutate to 8-oxoguanine. Since the prevalence of this altered nucleotide is often used as a biomarker for oxidative DNA damage, researchers were surprised to find significantly high levels of 8-oxoguanine in the DNA of neurons of people with Alzheimer’s disease.

How did these cells sustain so much oxidative damage? Several factors likely contributed to these mutations. One of the leading theories suggests that increased inflammation in the brain during Alzheimer’s disease exposes brain cells to high levels of oxygen-reactive species. In addition to building up -β and neurofibrillary tau proteins, repeated activation of the brain’s primary immune defense mechanism, microglia, has been shown to correlate with cognitive decline during Alzheimer’s disease. The presence of amyloid-β proteins reportedly triggers microglia to release not only cytokines, but also reactive oxygen species in an attempt to free up the extracellular space. As the disease progresses and proteins continue to accumulate, microglial cells never stop producing cytokines and reactive oxygen species, which consequently damage cells.

An important piece of the puzzle remains: What causes amyloid-β and tau to accumulate in the first place? Previous studies have shown that amyloid-β plaques can build up in the brain for up to 10 years before a person ever experiences symptoms. Yet there are several critical aspects of Alzheimer’s disease that we still don’t understand, including the mechanism by which the presence of amyloid β and tau proteins trigger inflammation and oxidative stress. The findings of this study bring us one step closer to unraveling these mysteries.

More than six million Americans currently have Alzheimer’s disease, although current projections warn that this neurodegenerative disease will become more common as a larger portion of the population ages and lives longer. Even if we can’t prevent the formation of amyloid-β and tau proteins in the first place, we can at least develop treatments that reduce the level of oxidative damage in the brain and extend the life expectancy of those with these and other diagnoses. . neurodegenerative disorders.

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