Repository logo
 

Does Soluble TREM2 Protect Against Alzheimer's Disease?

Simple item page
cam.depositDate2022-01-02
cam.issuedOnline2022-01-28
cam.oa.sapoa_rrs_na
cam.orpheus.counter1
cam.orpheus.successThu Feb 24 18:06:35 GMT 2022 - Embargo updated
datacite.ispreviousversionof.handlehttps://www.repository.cam.ac.uk/handle/1810/333907
dc.contributor.authorBrown, Guy C
dc.contributor.authorSt George-Hyslop, Peter
dc.contributor.orcidBrown, Guy [0000-0002-3610-1730]
dc.date.accessioned2022-01-05T00:32:27Z
dc.date.available2022-01-05T00:32:27Z
dc.date.issued2021
dc.date.updated2022-01-02T15:30:44Z
dc.description.abstractTriggering 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.
dc.description.sponsorshipEU IMI2
dc.identifier.doi10.17863/CAM.79413
dc.identifier.eissn1663-4365
dc.identifier.issn1663-4365
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331964
dc.language.isoeng
dc.publisherFrontiers Media
dc.publisher.departmentDepartment of Biochemistry
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAlzheimer's disease
dc.subjectTREM2
dc.subjectamyloid beta
dc.subjectmicroglia
dc.subjectneurodegeneration
dc.subjectneuroinflammation
dc.subjectneuroprotection
dc.subjectsTREM2
dc.titleDoes Soluble TREM2 Protect Against Alzheimer's Disease?
dc.typeArticle
dcterms.dateAccepted2021-12-31
prism.publicationNameFront Aging Neurosci
pubs.funder-project-idWellcome Trust (084645/Z/08/Z)
pubs.funder-project-idMedical Research Council (MR/L010593/1)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Research Infrastructures (RI) (115976)
pubs.funder-project-idWellcome Trust (203249/Z/16/Z)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.3389/fnagi.2021.834697

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
sTREM.Frontiers.pdf
Size:
421.35 KB
Format:
Adobe Portable Document Format
Description:
Accepted version
Licence
https://creativecommons.org/licenses/by/4.0/
Download

Collections

Cambridge University Research Outputs