Brain macrophages in Alzheimer's disease: from ontogeny to function
In the Alzheimer’s disease (AD) brain, microglia and border-associated macrophages (BAMs) undergo dynamic identity changes and display distinct activation and functional (or dysfunctional) states, which remains to be fully elucidated. Using an APP-KI AD mouse model, we demonstrated that microglia an...
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| Format: | Thesis-Doctor of Philosophy |
| Language: | English |
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Nanyang Technological University
2024
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| Online Access: | https://hdl.handle.net/10356/176738 |
| _version_ | 1811680872316796928 |
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| author | Wu, Xiaoting |
| author2 | Ruedl Christiane |
| author_facet | Ruedl Christiane Wu, Xiaoting |
| author_sort | Wu, Xiaoting |
| collection | NTU |
| description | In the Alzheimer’s disease (AD) brain, microglia and border-associated macrophages (BAMs) undergo dynamic identity changes and display distinct activation and functional (or dysfunctional) states, which remains to be fully elucidated. Using an APP-KI AD mouse model, we demonstrated that microglia and activated CD11c+ microglia were monocyte-independent and maintained their yolk-sac origin by self-renewal. At the brain borders, the embryonic-derived BAMs were minimally replaced by bone marrow (BM)-derived cells in adulthood, except for dura mater (DM) macrophages, whose niche allowed monocyte replenishment. Concerning functional states, we identified a propensity of macrophages to accumulate lipid droplets (LD) in the AD brain, which inversely correlates with their phagocytic activity. Using an inducible transgenic mouse model, we successfully reduced the lipid load in CX3CR1+ microglia and BAMs, which enhanced their phagocytic and efferocytic capabilities. This functional rewiring of brain macrophages resulted in a significant reduction of Aβ deposition in AD mouse brains. Therefore, targeting the lipid accumulation in microglia could potentially be exploited as a therapeutic strategy for treating AD. |
| first_indexed | 2024-10-01T03:31:57Z |
| format | Thesis-Doctor of Philosophy |
| id | ntu-10356/176738 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:31:57Z |
| publishDate | 2024 |
| publisher | Nanyang Technological University |
| record_format | dspace |
| spelling | ntu-10356/1767382024-06-03T06:51:19Z Brain macrophages in Alzheimer's disease: from ontogeny to function Wu, Xiaoting Ruedl Christiane School of Biological Sciences Ruedl@ntu.edu.sg Medicine, Health and Life Sciences Alzheimer's disease Microglia Border-associated macrophages Ontogeny Lipid droplet In the Alzheimer’s disease (AD) brain, microglia and border-associated macrophages (BAMs) undergo dynamic identity changes and display distinct activation and functional (or dysfunctional) states, which remains to be fully elucidated. Using an APP-KI AD mouse model, we demonstrated that microglia and activated CD11c+ microglia were monocyte-independent and maintained their yolk-sac origin by self-renewal. At the brain borders, the embryonic-derived BAMs were minimally replaced by bone marrow (BM)-derived cells in adulthood, except for dura mater (DM) macrophages, whose niche allowed monocyte replenishment. Concerning functional states, we identified a propensity of macrophages to accumulate lipid droplets (LD) in the AD brain, which inversely correlates with their phagocytic activity. Using an inducible transgenic mouse model, we successfully reduced the lipid load in CX3CR1+ microglia and BAMs, which enhanced their phagocytic and efferocytic capabilities. This functional rewiring of brain macrophages resulted in a significant reduction of Aβ deposition in AD mouse brains. Therefore, targeting the lipid accumulation in microglia could potentially be exploited as a therapeutic strategy for treating AD. Doctor of Philosophy 2024-05-17T08:08:40Z 2024-05-17T08:08:40Z 2024 Thesis-Doctor of Philosophy Wu, X. (2024). Brain macrophages in Alzheimer's disease: from ontogeny to function. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/176738 https://hdl.handle.net/10356/176738 10.32657/10356/176738 en This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). application/pdf Nanyang Technological University |
| spellingShingle | Medicine, Health and Life Sciences Alzheimer's disease Microglia Border-associated macrophages Ontogeny Lipid droplet Wu, Xiaoting Brain macrophages in Alzheimer's disease: from ontogeny to function |
| title | Brain macrophages in Alzheimer's disease: from ontogeny to function |
| title_full | Brain macrophages in Alzheimer's disease: from ontogeny to function |
| title_fullStr | Brain macrophages in Alzheimer's disease: from ontogeny to function |
| title_full_unstemmed | Brain macrophages in Alzheimer's disease: from ontogeny to function |
| title_short | Brain macrophages in Alzheimer's disease: from ontogeny to function |
| title_sort | brain macrophages in alzheimer s disease from ontogeny to function |
| topic | Medicine, Health and Life Sciences Alzheimer's disease Microglia Border-associated macrophages Ontogeny Lipid droplet |
| url | https://hdl.handle.net/10356/176738 |
| work_keys_str_mv | AT wuxiaoting brainmacrophagesinalzheimersdiseasefromontogenytofunction |