Longevity Briefs: How Inflammation Stops New Brain Cells From Growing

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

It was once believed that the adult brain couldn’t produce new neurons (neurogenesis). We now know that this isn’t true – in fact, our brain may retain the ability to grow neurons even into our 80s and beyond. Unfortunately, neurogenesis still declines with age, with severe implications for cognitive ageing and age-related neurodegenerative diseases. In the hippocampus (a brain region that is vital for learning and memory), neural stem cells continuously generate new neurons throughout life. These fresh neurons are necessary for the formation of new memories, but hippocampal neurogenesis deteriorates in old age, contributing to cognitive decline and Alzheimer’s disease.

Scientists know that one of the key drivers of this decline is inflammation. Inflammation is the immune system’s inaccurate (but effective) weapon for keeping pathogens at bay during the earlier stages of an infection. Inflammation is supposed to resolve after an infection, but in old age inflammation becomes sustained at low levels at all times, driving many age-related diseases. One of the key inflammatory signalling molecules that sustains this chronic inflammation is called tumour necrosis factor alpha (TNF-α), so named for its ability to kill tumours in cell culture. Scientists already knew that TNF-α could suppress neurogenesis in the hippocampus, but not how. In this study, researchers set out to answer this question, potentially also revealing some strategies for interfering with this suppression and restoring neurogenesis in the ageing brain.

The discovery:

Researchers started by exposing hippocampal progenitor cells to varying levels of TNF-α, mimicking the chronic inflammation seen in ageing brains, and studied their responses using RNA sequencing. This is when scientists look at the quantity of RNA – the genetic ‘templates’ that are used to produce proteins – in order to study gene activity. If they see more of a given RNA sequence, this means that the activity of the associated gene has increased and more of the associated protein is being produced.

Researchers found that exposure to TNF-α activated the expression of a gene called IFNB1 which encodes interferon beta (IFN-β), another inflammatory molecule that is primarily involved in fighting viral infections. IFN-β acts in an autocrine and paracrine way, meaning that it is released from a cell before binding to its receptors on that same cell and on neighbouring cells. This was associated with a reduction in the number of cells expressing doublecortin (a marker of neurogenesis) and also the release of chemokines (molecules that attract immune cells to the release site – something that is observed in Alzheimer’s disease).

The key finding was that this pathway could be interfered with. Researchers found that when they used an antibody called anifrolumab to block interferon receptors, T cells were no longer attracted towards the stem cells exposed to TNF-α, the number of doublecortin-expressing cells was restored to normal levels (suggesting restored neurogenesis).

Proportion of cells undergoing neurogenesis (doublecortin-positive, DCX+) among untreated hippocampal progenitor cells (control), anifrolumab-treated control cells, TNF-α -treated cells and cells treated with anifrolumab and TNF-α. ns indicates no statistical difference between the indicated groups.
*TNF-α induces type I IFN signalling to suppress neurogenesis and recruit T cells*

The implications:

This study reveals a previously unknown mechanism that could explain the link between inflammation, cognitive decline and dementia. IFN-β is usually released by cells when they are infected by a virus. This serves to ‘warn’ nearby cells, triggering a pre-emptive antiviral state to slow down the spread of the virus while recruiting immune cells to the site of the infection. It seems as though low levels of TNF-α may trigger this response in hippocampal progenitor cells, reprogramming them from a neurogenic state into an immune-defensive one.

There’s a large gap between what researchers did here and what it would take to show that this mechanism actually contributes to cognitive decline and dementia in humans. It’s also worth noting that this study was carried out in hippocampal stem cells derived from human foetuses, not from aged adults. Adult stem cells become defective in old age for a variety of reasons, so the effects of blocking IFN-β signalling in these cells may not be as impressive. That said, it is still a line of research worth exploring. If blocking IFN-β receptors is shown to preserve cognitive function in animal models, it may be worth exploring whether blocking some part of this pathway in humans can improve cognitive function in neurodegenerative disease. Blocking interferon receptors with anifrolumab is a strategy that is already used to treat the autoimmune disease Lupus, but is generally undesirable due to greatly increased risk of viral infection.

While this specific mechanism may not be proven in adult humans, it is widely accepted that higher levels of chronic inflammation increases the risk of cognitive decline and dementia. A lifestyle that suppresses inflammation (a plant-focussed diet rich in antioxidants, adequate exercise and sleep) is worth pursuing if you want to preserve cognitive function into old age.