@article{2608aea5434f473f9ca8511b34fc8cf0,
title = "Functional insights from biophysical study of TREM2 interactions with apoE and Aβ1-42",
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.",
keywords = "Alzheimer's disease, TREM2, amyloid beta, apolipoprotein E, microglia, neurodegeneration, neuroinflammation",
author = "Kober, {Daniel L.} and Stuchell-Brereton, {Melissa D.} and Kluender, {Colin E.} and Dean, {Hunter B.} and Strickland, {Michael R.} and Steinberg, {Deborah F.} and Nelson, {Samantha S.} and Berevan Baban and Holtzman, {David M.} and Carl Frieden and Jennifer Alexander-Brett and Roberson, {Erik D.} and Yuhua Song and Brett, {Tom J.}",
note = "Funding Information: This work was supported by the NIH [R01‐HL119813] (T.J.B), [T32‐GM007067] (D.L.K.), [T32‐GM008361] (H.B.D), [T32‐NS095775] (H.B.D), [K08‐HL121168] (J.A.B), Knight Alzheimer's Disease Research Center pilot grant [P50‐AG005681‐30.1] (T.J.B.), Alzheimer's Association Research Grant [AARG‐16‐441560] (T.J.B.), the American Heart Association Predoctoral Fellowships [15PRE22110004 and 17PRE32780001] (D.L.K.), the Burroughs‐Wellcome Fund Career Award for Medical Scientists (J.A.B.), and the Alzheimer's Drug Discovery Foundation [GC‐201804‐2015209] (E.D.R. & Y.S.). Funding Information: This work was supported by the NIH [R01-HL119813] (T.J.B), [T32-GM007067] (D.L.K.), [T32-GM008361] (H.B.D), [T32-NS095775] (H.B.D), [K08-HL121168] (J.A.B), Knight Alzheimer's Disease Research Center pilot grant [P50-AG005681-30.1] (T.J.B.), Alzheimer's Association Research Grant [AARG-16-441560] (T.J.B.), the American Heart Association Predoctoral Fellowships [15PRE22110004 and 17PRE32780001] (D.L.K.), the Burroughs-Wellcome Fund Career Award for Medical Scientists (J.A.B.), and the Alzheimer's Drug Discovery Foundation [GC-201804-2015209] (E.D.R. & Y.S.). Publisher Copyright: {\textcopyright} 2020 the Alzheimer's Association",
year = "2021",
month = mar,
doi = "10.1002/alz.12194",
language = "English",
volume = "17",
pages = "475--488",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
number = "3",
}