The research provides insights into how age-related cell senescence contributes to the progression of Alzheimer's disease.

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.

In a new study published in the journal Acta Neuropathologica researchers theorised that repeated damage to cells in the brain, which could be triggered by harmful proteins associated with Alzheimer’s, may promote senescence.

"Our study unveils a significant increase of premature senescence and associated molecular mechanisms in microglia." Dr Nurun Fancy Department of Brain Sciences

While previous research has suggested that Alzheimer’s could induce cell senescence, the cell types which could be affected and relationships with specific stressors were not understood. The scientists at the Department of Brain Sciences aimed to describe the affected cells and identify specific factors responsible.

Dr Nurun Fancy, Senior Bioinformatician and co-author of the study at the Department of Brain Sciences 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.”

Brain tissue and cell senescence

The researchers 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.

"Our work describes new targets for therapeutics, but also emphasises that emerging pharmacological approaches to increase autophagy could provide therapeutic benefits." Professor Paul Matthews Department of Brain Sciences

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.

Professor Paul Matthews, Edmond and Lily Safra Chair at the Deparment of Brain Sciences said: "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."

Fancy, N.N., Smith, A.M., Caramello, A. et al. Characterisation of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics. Acta Neuropathol 147, 78 (2024). https://doi.org/10.1007/s00401-024-02727-9

This article has been adapted from a news story by the UK Dementia Research Institute