A study led by Prof Paul Matthews and Dr Nurun Fancy (both UK DRI at Imperial) provides important new insights into the mechanisms by which a process known as age-related cell senescence contributes to the progression of Alzheimer’s disease. The study, published in the journal Acta Neuropathologica, could lead to new therapeutic targets for the condition.
What was the challenge?
Cell senescence is a process during which damaged cells resist removal by normal mechanisms, lingering and potentially causing harm to neighbouring healthy cells. Ageing is the greatest single risk factor for Alzheimer’s and is associated with cell senescence. The researchers theorised that repeated insults to cells in the brain, which could be triggered by harmful proteins associated with Alzheimer’s, may promote senescence.
While previous research has suggested that Alzheimer’s could induce cell senescence, the affected range of cell types and relationships with specific stressors were not understood. Prof Matthews’ team aimed to describe the affected cells and identify specific factors responsible.
Our work describes new targets for therapeutics, but also emphasises that emerging pharmacological approaches to increase autophagy could provide therapeutic benefits in part by reducing premature microglial senescence.Prof Paul MatthewsUK DRI at Imperial
What did the team do and what did they find?
The team characterised cell senescence in brain tissue from several regions of the cortex, in the brains of people with Alzheimer’s and healthy controls. They measured the expression levels of a known marker of senescence called beta-galactosidase and found that overall, it was expressed 4-5 times more in microglia, astrocytes and oligodendroglial cells in the Alzheimer’s brains. In addition, they found that microglia expressed markers of DNA damage in the Alzheimer’s brains.
The team found that the levels of senescence markers were increased in microglia that were found near amyloid plaques, a hallmark of Alzheimer’s. This indicates that Alzheimer’s disease can promote senescence, as well as be more easily initiated where there is senescence. Analysing the genes present in these microglia, the researchers found that genes working against autophagy and apoptosis, the normal mechanisms by which damaged cells are cleared away, were upregulated. Genes preventing senescence were down regulated.
Dr Fancy said:
"Our study unveils a significant increase of premature senescence and associated molecular mechanisms in microglia. This provides new insights into Alzheimer's disease progression. We have elucidated how amyloid beta exacerbates this senescence phenotype and highlighted potential therapeutic targets for Alzheimer's treatment."
What is the impact of these findings?
The study identifies how senescence is enhanced in microglia, the cell also most enriched for risk gene expression with Alzheimer’s. The findings suggest that amyloid beta reduces its own clearance, by reducing the ability of microglia to phagocytose, or eat, damaged or waste material – accelerating disease progression. The study suggests targets to modulate microglia as a future therapeutic strategy.
Prof Matthews added:
"Premature glial senescence provides a new paradigm for understanding the interaction between genes and environmental risk factors for Alzheimer’s disease. In this case, the results suggest how oxidative stress, which increases with a wide range of environmental (and co-morbid disease) insults, can interact with disease-specific processes to accelerate the progression of pathology.
Our work describes new targets for therapeutics, but also emphasises that emerging pharmacological approaches to increase autophagy could provide therapeutic benefits in part by reducing premature microglial senescence."
To find out more about Prof Paul Matthews’s research, visit his UK DRI profile. To keep up to date with the latest UK DRI news and events, sign up to receive our monthly newsletter.
Article published: 8 May 2024
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