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 from researchers at Brigham Women’s Hospital and Boston Children’s Hospital we may be one step closer to understanding why this happens.
Whole-genome sequencing of more than 300 brain cells uncovered significant oxidative DNA damage in the hippocampus and prefrontal cortex, two of the primary regions Alzheimer’s affects. Widespread mutations to the genome appear to be related to increased exposure to reactive oxidative species, produced in response to the accumulation of tau and amyloid-β proteins during Alzheimer’s. This study by Miller et al. not only sheds light on underlying mechanisms of Alzheimer’s disease but also the natural consequences of aging.
Oxidative DNA damage comes in different forms from both external and internal sources. Even normal cellular metabolic processes can produce superoxide byproducts, a molecule known to be a precursor for other reactive oxygen species. At low levels, reactive oxygen species have been shown to play a role in cell signaling and maintaining homeostasis. Allowing these molecules to accumulate in a cell, however, can disrupt cellular function, not to mention destabilize DNA. Although cells have developed ways to minimize the impact of reactive oxygen species, these mechanisms are not perfect. Repairing DNA regions with oxidative damage can also come at 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 of whether to repair the damage or leave it unrepaired.
DNA mutations are passed down each time a cell is regenerated and as a result, accumulate over time. Studies suggest that such mutations not only contribute to the aging process but also the development of some age-related diseases. Alzheimer’s disease, for example, is associated with extensive oxidative stress marked 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 located in the prefrontal cortex and hippocampus from the post-mortem brain samples of those with and without Alzheimer’s.
Compared to neurotypical adults, Miller et al.’s first investigation uncovered significantly more DNA mutations among those diagnosed with Alzheimer’s disease. As Dr. Michael B Miller, the lead author and professor of Pathology at Brigham, said, these “results suggest that AD neurons experience genomic damage that causes immense stress on cells and creates dysfunction among them. These findings may explain why many brain cells die during AD.”
DNA mutations can have significant consequences on the transcription, as well as expression, of genes. Transcription of an altered nucleotide may 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 may stop being expressed permanently. In fact, investigators found a greater prevalence of dysfunctional neurons with important genes that were no longer being expressed in those with Alzheimer’s compared to the neurotypical control group.
The DNA damage observed in individuals diagnosed with Alzheimer’s was beyond the pattern of damage associated with normal age-related mutations. Also, a greater portion of mutations among this group more often impacted genes that are important for neuron function, as well as survival. Investigators concluded that there are likely several mechanisms contributing to increased DNA mutations that may be specific to Alzheimer’s disease.
Although there was some evidence of increased age-related DNA changes, most of the damage investigators observed appeared to be a result of oxidative damage to nucleotides. In particular, DNA mutations commonly affect guanine nucleotides. When exposed to reactive oxygen species, these nucleotides may mutate into 8-oxoguanine. Given that the prevalence of this altered nucleotide is often used as a biomarker for oxidative DNA damage, investigators were surprised to find significantly high levels of 8-oxoguanine in the DNA of neurons from those with Alzheimer’s,
How did these cells acquire 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 exposes brain cells to high levels of oxygen reactive species. In addition to the buildup of -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 not only release cytokines but also reactive oxygen species in an attempt to clear the extracellular space. As the disease progresses and proteins continue to build up, microglial cells never cease producing cytokines and reactive oxygen species, which consequently damages cells.
One major piece of the puzzle remains: what causes amyloid-β and tau to build up in the first place? Previous studies have found that amyloid-β plaques can accumulate in the brain for up to 10 years before one ever experiences any symptoms. Yet, there are several critical aspects of Alzheimer’s disease that we still do not understand, including the mechanism through which the presence of amyloid-β and tau proteins induce inflammation and oxidative stress. The findings from this study do bring us one step closer to uncovering these mysteries.
More than six million Americans currently have Alzheimer’s, albeit current projections warn that this neurodegenerative disease will become increasingly common as more of the general population gets older and lives longer. Even if we cannot prevent amyloid-β and tau proteins from building up in the first place, we may at least be able to develop treatments that reduce the level of oxidative damage in the brain and prolong the life expectancy of those diagnosed with this and other neurodegenerative disorders.