Deletion of p38α in Neurons Slows Neural Stem Cell Decline and Loss of Cognitive Function in Mice

Researchers here provide evidence for p38α to be involved in the regulation of diminished neural stem cell activity with age. It is thought that the loss of stem cell activity with age, throughout the body and not just in the brain, is an evolved response to rising levels of damage that serves to reduce the risk of cancer that arises from the activity of damaged cells. The cost, however, is a slow decline into dysfunction and tissue failure. There are many therapeutic approaches under development in labs and startups that involve ways to force stem cell populations to go back to work, overriding their normal reaction to an aged environment. While this is nowhere as good a class of approach as repairing the underlying damage of aging, some of these types of therapy may turn out to produce large enough benefits to be worth the effort.

Neurogenesis occurs in the subgranular zone of the dentate gyrus (DG) in the hippocampus and the subventricular zone (SVZ) of the lateral ventricle in the adult mammalian brain. Adult hippocampal neurogenesis arises from neural stem cells (NSCs) within the DG. NSCs give rise to intermediate progenitor cells, which divide generating immature neurons that subsequently integrate into the local neural network as granule cells. Accumulating evidence suggests that adult-born neurons may play distinct physiological roles in hippocampus-dependent functions such as memory encoding and mood regulation. Age induces a decline in adult NSC activity and neuronal plasticity, which could partially explain some age-related cognitive deficit symptoms. Neuronal loss or dysfunction also contributes to the onset of age-related neurodegenerative pathologies.

Increasing evidence reveals that NSC activity is regulated by intrinsic and extrinsic factors. Among the latter, it has been recently shown that neuronal activity controls NSC quiescence and subsequently neurogenesis in the hippocampus. The molecular mechanism by which neuronal activity contributes to the regulation of NSCs, and whether this decreases with aging, remains unknown.

p38 mitogen-activated protein kinase (p38MAPK) is an important sensor of intrinsic and extrinsic stresses and consequently controls key processes of mammalian cell homeostasis such as self-renewal, differentiation, proliferation, and death. In the brain, p38MAPK signalling is activated during neurodegenerative diseases and in response to brain injury. Its genetic or pharmacological inhibition ameliorates symptoms of neurodegenerative diseases and protects against ischemia. The p38MAPK family comprises four members, with p38α and p38β being expressed at high levels in the brain. p38α has been involved in inflammation and environmental stresses, and there is evidence implicating p38α in neuronal function and cognitive activity with contradictory results.

Using mice, we demonstrate that genetic deletion of p38α in neurons suffices to reduce age-associated elevation of p38MAPK activity, neuronal loss and cognitive decline. Moreover, aged mice with genetic deletion of p38α present elevated numbers of NSCs in the hippocampus and the subventricular zone. These results reveal novel roles for neuronal p38MAPK in age-associated NSC exhaustion and cognitive decline.


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