Does Soluble TREM2 Protect Against Alzheimer's Disease?
Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor on myeloid cells, and is upregulated on microglia surrounding amyloid plaques in Alzheimer's disease (AD). Rare, heterozygous mutations in TREM2 (e.g., R47H) increase AD risk several fold. TREM2 can be cl...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2021.834697/full |
| _version_ | 1798024882398691328 |
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| author | Guy C. Brown Peter St George-Hyslop Peter St George-Hyslop |
| author_facet | Guy C. Brown Peter St George-Hyslop Peter St George-Hyslop |
| author_sort | Guy C. Brown |
| collection | DOAJ |
| description | Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor on myeloid cells, and is upregulated on microglia surrounding amyloid plaques in Alzheimer's disease (AD). Rare, heterozygous mutations in TREM2 (e.g., R47H) increase AD risk several fold. TREM2 can be cleaved at the plasma membrane by metalloproteases to release the ectodomain as soluble TREM2 (sTREM2). Wild-type sTREM2 binds oligomeric amyloid beta (Aβ) and acts as an extracellular chaperone, blocking and reversing Aβ oligomerization and fibrillization, and preventing Aβ-induced neuronal loss in vitro. Whereas, R47H sTREM2 increases Aβ fibrillization and neurotoxicity. AD brains expressing R47H TREM2 have more fibrous plaques with more neuritic pathology around these plaques, consistent with R47H sTREM2 promoting Aβ fibrillization relative to WT sTREM2. Brain expression or injection of wild-type sTREM2 reduces pathology in amyloid models of AD in mice, indicating that wild-type sTREM2 is protective against amyloid pathology. Levels of sTREM2 in cerebrospinal fluid (CSF) fall prior to AD, rise in early AD, and fall again in late AD. People with higher sTREM2 levels in CSF progress more slowly into and through AD than do people with lower sTREM2 levels, suggesting that sTREM2 protects against AD. However, some of these experiments can be interpreted as full-length TREM2 protecting rather than sTREM2, and to distinguish between these two possibilities, we need more experiments testing whether sTREM2 itself protects in AD and AD models, and at what stage of disease. If sTREM2 is protective, then treatments could be designed to elevate sTREM2 in AD. |
| first_indexed | 2024-04-11T18:09:46Z |
| format | Article |
| id | doaj.art-7cc45101dffe4ce69d803f10df62d3fc |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-04-11T18:09:46Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-7cc45101dffe4ce69d803f10df62d3fc2022-12-22T04:10:11ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652022-01-011310.3389/fnagi.2021.834697834697Does Soluble TREM2 Protect Against Alzheimer's Disease?Guy C. Brown0Peter St George-Hyslop1Peter St George-Hyslop2Department of Biochemistry, University of Cambridge, Cambridge, United KingdomDepartment of Medicine, University of Cambridge, Cambridge, United KingdomDepartment of Medicine, University of Toronto, Toronto, ON, CanadaTriggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor on myeloid cells, and is upregulated on microglia surrounding amyloid plaques in Alzheimer's disease (AD). Rare, heterozygous mutations in TREM2 (e.g., R47H) increase AD risk several fold. TREM2 can be cleaved at the plasma membrane by metalloproteases to release the ectodomain as soluble TREM2 (sTREM2). Wild-type sTREM2 binds oligomeric amyloid beta (Aβ) and acts as an extracellular chaperone, blocking and reversing Aβ oligomerization and fibrillization, and preventing Aβ-induced neuronal loss in vitro. Whereas, R47H sTREM2 increases Aβ fibrillization and neurotoxicity. AD brains expressing R47H TREM2 have more fibrous plaques with more neuritic pathology around these plaques, consistent with R47H sTREM2 promoting Aβ fibrillization relative to WT sTREM2. Brain expression or injection of wild-type sTREM2 reduces pathology in amyloid models of AD in mice, indicating that wild-type sTREM2 is protective against amyloid pathology. Levels of sTREM2 in cerebrospinal fluid (CSF) fall prior to AD, rise in early AD, and fall again in late AD. People with higher sTREM2 levels in CSF progress more slowly into and through AD than do people with lower sTREM2 levels, suggesting that sTREM2 protects against AD. However, some of these experiments can be interpreted as full-length TREM2 protecting rather than sTREM2, and to distinguish between these two possibilities, we need more experiments testing whether sTREM2 itself protects in AD and AD models, and at what stage of disease. If sTREM2 is protective, then treatments could be designed to elevate sTREM2 in AD.https://www.frontiersin.org/articles/10.3389/fnagi.2021.834697/fullTREM2sTREM2microgliaAlzheimer's diseaseamyloid betaneuroinflammation |
| spellingShingle | Guy C. Brown Peter St George-Hyslop Peter St George-Hyslop Does Soluble TREM2 Protect Against Alzheimer's Disease? Frontiers in Aging Neuroscience TREM2 sTREM2 microglia Alzheimer's disease amyloid beta neuroinflammation |
| title | Does Soluble TREM2 Protect Against Alzheimer's Disease? |
| title_full | Does Soluble TREM2 Protect Against Alzheimer's Disease? |
| title_fullStr | Does Soluble TREM2 Protect Against Alzheimer's Disease? |
| title_full_unstemmed | Does Soluble TREM2 Protect Against Alzheimer's Disease? |
| title_short | Does Soluble TREM2 Protect Against Alzheimer's Disease? |
| title_sort | does soluble trem2 protect against alzheimer s disease |
| topic | TREM2 sTREM2 microglia Alzheimer's disease amyloid beta neuroinflammation |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2021.834697/full |
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