Why does Alzheimer's disease kill so many brain cells?

▎WuXi AppTec Content Team Editor This week, an important paper on Alzheimer's disease was published in the top academic journal "Nature", providing an explanation for a core problem of Alzheimer's disease: why Alzheimer's disease Do nerve cells die in the brains of sick patients? The researchers pointed out that this discovery not only provides a new window for understanding the pathogenesis of Alzheimer's disease, but also points out a new way for the treatment of Alzheimer's disease
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Alzheimer's disease is a neurodegenerative disease that often threatens the elderly, causing cognitive decline, memory loss, abnormal behavior and other symptoms, and it will get worse
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The main reason behind this is that the disease leads to irreversible death of neurons in the brain
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In the new study, a team of researchers at Brigham and Women's Hospital and Boston Children's Hospital measured the mutations that develop in the brain's nerve cells to suggest a cause of brain cell death in Alzheimer's patients.
The real reason is the unusually rapid accumulation of somatic mutations
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Image credit: 123RF cells During normal growth, DNA inevitably makes some mistakes
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These errors, called somatic mutations, accumulate with age
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The nerve cells of the brain are no exception, accumulating mutations at a rate during aging
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But in this study, the scientists found that, affected by Alzheimer's disease, the somatic mutations accumulated in nerve cells in the brains of patients were abnormal in both speed and type
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The researchers performed single-cell whole-genome sequencing analysis of hundreds of neurons in the hippocampus and prefrontal cortex, two of the main brain regions affected by the disease
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The analysis showed that compared with age-matched controls without neurological disease, nerve cells affected by Alzheimer's disease had more changes in their DNA, mostly in what are known as single-nucleotide variants (single-nucleotide variants).
sSNV) type
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▲ Schematic diagram of the experimental process for measuring somatic mutations in brain neurons (Image source: Reference [1]) The researchers continued to trace the source of these mutations
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In theory, a large number of mutations in nerve cells usually result from increased DNA oxidation
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Therefore, the researchers identified 8-oxoguanine, an indicator of oxidative stress and DNA damage
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The results showed that neurons affected by Alzheimer's disease did have increased levels of oxidation
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Judging from the results of the accumulation of mutations in nerve cells, the researchers' preliminary analysis found that these additional changes can affect the genes encoded by DNA, causing gene inactivation and imbalance of intracellular protein homeostasis, ultimately impairing neuronal function
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"These results suggest that disease-affected neurons have substantial oxidative damage and somatic mutations, which may be important contributors to the development of Alzheimer's disease pathology,
"
the researchers noted
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▲ This study proposes a model for the role of somatic mutations in the pathogenesis of Alzheimer's disease (Image source: Reference [1]) "The genomic damage suffered by neurons in patients with Alzheimer's disease causes cell damage.
Huge stress causes dysfunction of nerve cells
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These findings could explain why many brain cells die during Alzheimer's progression
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"In the future, we are eager to further elucidate how the mutations observed in Alzheimer's disease neurons lead to neuronal cell death, and work to identify ways to target this pathway," concludes Michael B.
Miller, PhD, lead author of the study.
new therapy
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"Reference: [1] Michael B.
Miller et al.
, (2022) Somatic genomic changes in single Alzheimer's disease neurons.
Nature Doi: https://doi.
org/10.
1038/s41586-022-04640-1[2] Genetic changes differed, increased in people with Alzheimer's disease.
Retrieved Apr.
20, 2022 from https://