Adult mammalian brains eke out limited numbers of new neurons in select regions, but over time, even that production dwindles. Why is unclear. New evidence from the lab of Anne Brunet, Stanford University, California, suggests invading immune cells may play a part. In the July 4 Nature, Brunet and colleagues report that T cells, absent from the brains of young mice, show up in the subventricular zone of old animals. Neurogenesis then slows to a halt. The T cells secrete the proinflammatory cytokine interferon-γ, which prevents neural stem cells from proliferating. Though the exact mechanism has yet to be worked out, this might be one reason neurogenesis takes a hit in aging, the authors wrote.

  • Single-cell RNA-Seq identified T cells in the neurogenic zone of old mice.
  • T cells correlated with less neurogenesis and major transcriptional shifts.
  • The immune cells secreted the inflammatory cytokine interferon-γ.

“These findings are extremely important,” said Evgenia Salta, KU Leuven, Belgium, who was not involved in the study. “Now, we can start mechanistically dissecting the regulators of the decline in neurogenesis to see if we can use them to rejuvenate the brain.” However, she pointed out that the main neurogenic site in the human brain is the dentate gyrus, a niche that has been reported to be less active upon aging and in AD, as well as being linked to memory and cognition. T cells could similarly suppress neurogenesis in the dentate gyrus, she said, but that would need to be assessed.

Orly Lazarov, University of Illinois, Chicago, agreed. She noted there may be differences between the blood-brain barrier of the subventricular zone (SVZ) and dentate gyrus, which could be important in regulating T-cell infiltration into the parenchyma. “It would be interesting to compare and contrast the effect of aging on the two neurogenic niches in light of differences in the BBB composition and level of interaction with and penetration from the circulation,” she wrote to Alzforum.

Distinct Cell Types. Stochastic neighbor embedding (SNE) plots transcriptomic relationships in two dimensions; the closer the dots, the more similar the transcriptomes. Eleven cell types fill the SVZ of old and young mice, where T cells (red) come almost exclusively from old mice. [Courtesy of Dulken et al., 2019.]

Age-related thinning, signaling changes, and decreased neural progenitor proliferation have all been reported in the subventricular zone of mice (Luo et al., 2006; Enwere et al., 2004; Molofsky et al., 2006). However, a detailed account of how aging affects single cells within this region has never been done. Brunet’s group, including first author Ben Dulken, now completing his M.D./Ph.D. at Stanford University School of Medicine, wanted to rectify this.

To do this, they compared three 3-month-old and three 28-month-old mice. The researchers dissociated the cells of the SVZ and analyzed their transcriptomes by single-cell RNA-Seq. This revealed 11 specific cell types, including activated neural stem cells (aNSCs)/neuroprogenitors (NPCs), neuroblasts, neurons, oligodendrocyte precursors, mature oligodendrocytes, endothelial cells, mural cells, microglia, macrophages, and T cells. There were major transcriptional differences between the young and old animals—especially among the endothelial cells, oligodendrocytes, and microglia—as well as a 75 percent reduction in the number of aNSCs, NPCs, and neuroblasts.

The T cells only appeared in the old mice. Immunostaining revealed them to be in the brain parenchyma, not the vasculature, in close proximity to NSCs. Many of these T cells expressed similar sets of T cell receptors, suggesting they may have originated by clonal expansion, possibly in response to a specific antigen. They expressed different receptors than did T cells in the blood, an indication these cells proliferated in the brain.

Unlike blood T cells, these brain types expressed high levels of the inflammatory cytokine interferon-γ. Since several cell types in the neurogenic niche of old mice expressed the receptor for interferon-γ, as well as the downstream protein STAT1, they likely respond to the cytokine. A subset of cells that was particularly responsive to interferon-γ expressed fewer cell-cycle transcripts and proliferated less, suggesting IFN-γ suppressed cell division. In a dish, T cells cut proliferation of NSCs by 90 percent. An antibody to IFN-γ restored proliferation. All told, the results suggest that in old mice, IFN-γ secreted by T cells prevents proliferation of NSCs.

The researchers found T cells in human brains in the lining of the lateral ventricles, which is also thought to generate newborn neurons (Ernst et al., 2014). This suggests a similar mechanism could suppress neurogenesis in the aging human brain.

“Dulken and colleagues’ work adds to a growing body of evidence that points to interactions between immune cells and stem cells as a cause of age-related decline in tissue function,” wrote Allison Bond and Hongjun Song, University of Pennsylvania, Philadelphia, in an accompanying News & Views. “Perhaps therapies can be developed to target the immune system as a way of combating aging-related stem-cell deficits throughout the body,” they wrote.—Gwyneth Dickey Zakaib

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References

Paper Citations

  1. . The aging neurogenic subventricular zone. Aging Cell. 2006 Apr;5(2):139-52. PubMed.
  2. . Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci. 2004 Sep 22;24(38):8354-65. PubMed.
  3. . Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature. 2006 Sep 28;443(7110):448-52. PubMed.
  4. . Neurogenesis in the striatum of the adult human brain. Cell. 2014 Feb 27;156(5):1072-83. Epub 2014 Feb 20 PubMed.

Further Reading

Papers

  1. . Single-Cell Transcriptomics Characterizes Cell Types in the Subventricular Zone and Uncovers Molecular Defects Impairing Adult Neurogenesis. Cell Rep. 2018 Nov 27;25(9):2457-2469.e8. PubMed.
  2. . Single-cell transcriptomics reveals gene signatures and alterations associated with aging in distinct neural stem/progenitor cell subpopulations. Protein Cell. 2018 Apr;9(4):351-364. Epub 2017 Jul 26 PubMed.

Primary Papers

  1. . Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature. 2019 Jul 3; PubMed.
  2. . Infiltration of old brains by T cells causes dysfunction of neural stem cells. Nature News & Views, 03 July 2019