Microglia in the Aged Subventricular Zone Acquire a Disease Associated Transcriptome – Implications for Neurogenesis
(2021) MOBN03 20202Degree Projects in Molecular Biology
- Abstract
- Neurogenesis, the formation of new neurons from neural stem cells, persists throughout life but with a rapid reduction during aging. With such a reduction, decline in cognitive abilities and the occurrence of neurodegenerative diseases are imminent. It is, therefore, important to better understand the role of key factors involved in the reduction of neurogenesis during aging. Microglia, the brain-resident macrophages, influencers of neurogenesis, exist as two subpopulations, IBA1+ and IBA1-, in the murine subventricular zone (SVZ). Chronic inflammation and an increase in IBA1+ microglia cells have been shown to reduce neurogenesis in the aged SVZ. However, age-related changes of the potentially neurogenic, IBA1- subpopulation, has not been... (More)
- Neurogenesis, the formation of new neurons from neural stem cells, persists throughout life but with a rapid reduction during aging. With such a reduction, decline in cognitive abilities and the occurrence of neurodegenerative diseases are imminent. It is, therefore, important to better understand the role of key factors involved in the reduction of neurogenesis during aging. Microglia, the brain-resident macrophages, influencers of neurogenesis, exist as two subpopulations, IBA1+ and IBA1-, in the murine subventricular zone (SVZ). Chronic inflammation and an increase in IBA1+ microglia cells have been shown to reduce neurogenesis in the aged SVZ. However, age-related changes of the potentially neurogenic, IBA1- subpopulation, has not been studied. Further, fractalkine receptor, CX3CR1, highly expressed by microglia, known to support neurogenesis in the hippocampus, has not been well studied in the SVZ. Thus, we wanted to understand whether there are any age-related changes in the IBA1- subpopulation that could potentially impact neurogenesis, and if CX3CR1 signaling supports neurogenesis in the aged SVZ. In our study, we identified and compared the single-cell transcriptomic profiles of microglial subpopulations in the young and aged SVZ and, found that the aged Iba1- and Iba1+ cells are very similar and show, the anti-neurodegenerative, Disease-Associated Microglia (DAM) signatures. Additionally, through immunohistochemistry, we observed no change in IBA1- subpopulation size in aged SVZ. In a comparison of neurogenesis between aged Cx3cr1-/- , Cx3cr1+/- and Cx3cr1+/+ mice, we observed a significant increase in neurogenesis with the loss of Cx3cr1. Our results, indicate the occurrence of DAM signatures during normal aging, and show a negative role of CX3CR1 signaling in neurogenesis during aging. (Less)
- Popular Abstract
- The Good cop and Bad cop of your aging brain
Ever wondered why your ability to learn diminishes with age? Or what makes old age prone to diseases in the brain? While there are several explanations, among the most important of them is that an old brain does not meet its demand for new nerve cells. A thorough understanding of what obstructs such production during aging would be important in combating numerous neurological diseases, if not just improve quality of life. We explored the role of Janus-faced immune cells of the brain, microglia, in obstructing the production of new nerve cells
New nerve cells are vital, be it in making new memories when you learn, or in substituting dying nerve cells. In specific regions of the brain, stem... (More) - The Good cop and Bad cop of your aging brain
Ever wondered why your ability to learn diminishes with age? Or what makes old age prone to diseases in the brain? While there are several explanations, among the most important of them is that an old brain does not meet its demand for new nerve cells. A thorough understanding of what obstructs such production during aging would be important in combating numerous neurological diseases, if not just improve quality of life. We explored the role of Janus-faced immune cells of the brain, microglia, in obstructing the production of new nerve cells
New nerve cells are vital, be it in making new memories when you learn, or in substituting dying nerve cells. In specific regions of the brain, stem cells reside, and produce new nerve cells throughout life. During aging, however, several changes happen in the body at a molecular level that reduce the production of nerve cells from stem cells. Importantly, microglia, the immune cells, or rather the police force in the brain, are known to take part in such obstruction.
Microglia, in good times, perform extreme roles; depending on local signals, they eat up dying nerve cells, or protect healthy nerve cells. Further, the microglia present in stem cell-residing regions, also specialize to promote the production of new nerve cells. Interestingly, in one of the stem-cell residing regions, microglia exist as two types, each representing one of the extreme roles, identified by the presence or absence of a specific protein, IBA1. While the IBA1 microglia, known to eat malformed precursors of nerve cells, during aging, change and prevent stem cells from forming new nerve cells, it is unknown if the IBA1-lacking microglia undergo such changes. In fact, the latter is regarded to promote formation of new nerve cells in young mice.
We compared the changes in gene expression of the IBA1-lacking microglia between young and aged mice to understand what implications it has. Much to our surprise, we discovered that while the two types of microglia in young animals were quite different, they become very similar in the aged brain. Do IBA1-lacking microglia obstruct the formation of new nerve cells? Given their similarity to IBA1 microglia, they most likely do. In fact, when we removed a gene important for microglia-stem cell communication, there was an increase in the number of nerve cell precursors, strengthening previous findings that microglia obstruct nerve cell production. However, in contrast to previously described age-related changes in microglia, that they eat healthy nerve cells, we found, that in stem cell-residing region, they, in fact, are protective and can prevent neurological diseases. Isn’t this contradictory? Based on previous research, we speculate that microglia, during aging, obstruct the production of nerve cells by releasing local signals that tell stem cells not to produce, rather than eating healthy nerve cell precursors.
Our results are important in that they improve our understanding of age-related changes in the brain and its consequence on nerve cell formation. Although our study has been in mice, the similarity between humans and mice makes it easier to verify the same in humans. Thus, these results bring us a step closer to developing therapy for combating the impact of aging on brain.
Master’s Degree Project in Molecular Biology 60 credits 2021
Department of Biology Lund University
Supervisors: Henrik Ahlenius and Jonas Fritze
Stem Cell Aging and Neurodegeneration Lab, Lund Stem Cell Center (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9059981
- author
- Muralidharan, Chandramouli
- supervisor
- organization
- course
- MOBN03 20202
- year
- 2021
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9059981
- date added to LUP
- 2021-06-30 12:38:04
- date last changed
- 2021-06-30 12:38:04
@misc{9059981,
abstract = {{Neurogenesis, the formation of new neurons from neural stem cells, persists throughout life but with a rapid reduction during aging. With such a reduction, decline in cognitive abilities and the occurrence of neurodegenerative diseases are imminent. It is, therefore, important to better understand the role of key factors involved in the reduction of neurogenesis during aging. Microglia, the brain-resident macrophages, influencers of neurogenesis, exist as two subpopulations, IBA1+ and IBA1-, in the murine subventricular zone (SVZ). Chronic inflammation and an increase in IBA1+ microglia cells have been shown to reduce neurogenesis in the aged SVZ. However, age-related changes of the potentially neurogenic, IBA1- subpopulation, has not been studied. Further, fractalkine receptor, CX3CR1, highly expressed by microglia, known to support neurogenesis in the hippocampus, has not been well studied in the SVZ. Thus, we wanted to understand whether there are any age-related changes in the IBA1- subpopulation that could potentially impact neurogenesis, and if CX3CR1 signaling supports neurogenesis in the aged SVZ. In our study, we identified and compared the single-cell transcriptomic profiles of microglial subpopulations in the young and aged SVZ and, found that the aged Iba1- and Iba1+ cells are very similar and show, the anti-neurodegenerative, Disease-Associated Microglia (DAM) signatures. Additionally, through immunohistochemistry, we observed no change in IBA1- subpopulation size in aged SVZ. In a comparison of neurogenesis between aged Cx3cr1-/- , Cx3cr1+/- and Cx3cr1+/+ mice, we observed a significant increase in neurogenesis with the loss of Cx3cr1. Our results, indicate the occurrence of DAM signatures during normal aging, and show a negative role of CX3CR1 signaling in neurogenesis during aging.}},
author = {{Muralidharan, Chandramouli}},
language = {{eng}},
note = {{Student Paper}},
title = {{Microglia in the Aged Subventricular Zone Acquire a Disease Associated Transcriptome – Implications for Neurogenesis}},
year = {{2021}},
}