Functional insights from biophysical study of TREM2 interactions with apoE and Aβ1‐42. Issue 3 (8th October 2020)

• Record Type: Journal Article
• Authors: Kober, Daniel L.; Stuchell‐Brereton, Melissa D.; Kluender, Colin E.; Dean, Hunter B.; Strickland, Michael R.; Steinberg, Deborah F.; Nelson, Samantha S.; Baban, Berevan; Holtzman, David M.; Frieden, Carl; Alexander‐Brett, Jennifer; Roberson, Erik D.; Song, Yuhua; Brett, Tom J.
• Is Part Of: Alzheimer's & dementia. Volume 17:Issue 3(2021)
• Page Start: 475
• Page End: 488
• Publication Date: 2020-10-08
• Subjects: Alzheimer's disease -- amyloid beta -- apolipoprotein E -- microglia -- neurodegeneration -- neuroinflammation -- TREM2; Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.12194
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Introduction: Triggering receptor expressed on myeloid cells‐2 (TREM2) is an immune receptor expressed on microglia that also can become soluble (sTREM2). How TREM2 engages different ligands remains poorly understood. Methods: We used comprehensive biolayer interferometry (BLI) analysis to investigate TREM2 and sTREM2 interactions with apolipoprotein E (apoE) and monomeric amyloid beta (Aβ) (mAβ42). Results: TREM2 engagement of apoE was protein mediated with little effect of lipidation, showing slight affinity differences between isoforms (E4 > E3 > E2). Another family member, TREML2, did not bind apoE. Disease‐linked TREM2 variants within a "basic patch" minimally impact apoE binding. Instead, TREM2 uses a unique hydrophobic surface to bind apoE, which requires the apoE hinge region. TREM2 and sTREM2 directly bind mAβ42 and potently inhibit Aβ42 polymerization, suggesting a potential role for soluble sTREM2 in preventing AD pathogenesis. Discussion: These findings demonstrate that TREM2 has at least two ligand‐binding surfaces that might be therapeutic targets and uncovers a potential function for sTREM2 in directly inhibiting Aβ polymerization.