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Mechanisms of stem cell proliferation and senescence in the aged and damaged mouse brain

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Ageing stem cells and neurodegeneration

The regenerative capacity of the adult brain is limited and decreases with age. An EU-funded project is investigating the mechanisms of senescence-related changes in the stem cells in the brain.

Health

Brain damage and neurodegeneration are the major causes of mortality and morbidity. A continuous production of neurons by neural stem cells is necessary to repair neurodegeneration, but this capacity is reduced in aged stem cells. Understanding the mechanisms controlling stem cell proliferation and senescence is of high priority for the development of stem cell-based therapies. The EU-funded AGING STEM CELLS (Mechanisms of stem cell proliferation and senescence in the aged and damaged mouse brain) project investigated such senescence-related mechanisms. It focused on the processes in an ageing and damaged brain involving the histone H2AX. As neural stem cell proliferation decreases with age, cumulative telomere erosion activates DNA damage response proteins, including H2AX. Researchers showed that H2AX has a protective effect in the maintenance of stem cell number throughout life. Thus, the number of stem cells was reduced in the brains of old animals lacking H2AX compared to wild-type mice of the same age. Additional evidence came from the fact that old H2AX-deficient mice had impaired olfactory memory. In addition to animal models, AGING STEM CELLS generated primary embryonic fibroblast cultures from H2AX mutant mice. Scientists used primary culture to study the importance of single mutations for cell proliferation, population growth and cell cycle progression. Another project priority was stroke protection. AGING STEM CELLS investigated the potential of GABAA receptors (ion channels responding to neurotransmitter gamma aminobutyric acid) for brain cell regeneration. For this, scientists studied whether the GABAA receptor antagonist bicuculline could affect neuronal outcome in a mouse stroke model. They found that bicuculline treatment indeed led to a higher number of immature neurons in the site of lesion seven weeks after the stroke. Thus, early blockade of GABAA receptors can be beneficial in the recovery stage of a stroke episode. Understanding age-related neurogenic decline and studying the possibilities to boost neurogenesis may open the way for new clinically relevant strategies for brain damage and neurodegeneration.

Keywords

Ageing, stem cells, neurodegeneration, senescence, brain damage, stroke

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9 October 2020