{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:58:22Z","timestamp":1761897502073,"version":"build-2065373602"},"reference-count":62,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1842605,"],"award-info":[{"award-number":["1842605,"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biosensors"],"abstract":"<jats:p>We report an effective surface immobilization protocol for capture of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a receptor whose elevated concentration in cerebrospinal fluid has recently been associated with Alzheimer\u2019s disease (AD). We employ the proposed surface functionalization scheme to design, fabricate, and assess a biochemical sensing platform based on plasmonic interferometry that is able to detect physiological concentrations of TREM2 in solution. These findings open up opportunities for label-free biosensing of TREM2 in its soluble form in various bodily fluids as an early indicator of the onset of clinical dementia in AD. We also show that plasmonic interferometry can be a powerful tool to monitor and optimize surface immobilization schemes, which could be applied to develop other relevant antibody tests.<\/jats:p>","DOI":"10.3390\/bios11070217","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T12:03:27Z","timestamp":1625141007000},"page":"217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Plasmonic Interferometers as TREM2 Sensors for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"11","author":[{"given":"Dingdong","family":"Li","sequence":"first","affiliation":[{"name":"School of Engineering, Brown University, 184 Hope St, Providence, RI 02912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Odessey","sequence":"additional","affiliation":[{"name":"School of Engineering, Brown University, 184 Hope St, Providence, RI 02912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongfang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Engineering, Brown University, 184 Hope St, Providence, RI 02912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domenico","family":"Pacifici","sequence":"additional","affiliation":[{"name":"School of Engineering, Brown University, 184 Hope St, Providence, RI 02912, USA"},{"name":"Department of Physics, Brown University, 182 Hope St, Providence, RI 02912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1016\/S0140-6736(16)31678-6","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990\u20132015: A systematic analysis for the Global Burden of Disease Study 2015","volume":"388","author":"Vos","year":"2016","journal-title":"Lancet"},{"unstructured":"World Health Organization (2018). Towards a Dementia Plan: A WHO Guide, World Health Organization.","key":"ref_2"},{"doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2017). 2017 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dement., 13, 325\u2013373.","key":"ref_3","DOI":"10.1016\/j.jalz.2017.02.001"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nrd4570","article-title":"What does it take to produce a breakthrough drug?","volume":"14","author":"Calcoen","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","first-page":"17","article-title":"Validation of clinical diagnostic criteria for Alzheimer\u2019s disease","volume":"24","author":"Morris","year":"1988","journal-title":"Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"349ps15","DOI":"10.1126\/scitranslmed.aaf2608","article-title":"Disciplined approach to drug discovery and early development","volume":"8","author":"Plenge","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"214.e7","DOI":"10.1016\/j.neurobiolaging.2016.07.018","article-title":"Polygenic score prediction captures nearly all common genetic risk for Alzheimer\u2019s disease","volume":"49","author":"Shoai","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/gim.2015.117","article-title":"The genetic landscape of Alzheimer disease: Clinical implications and perspectives","volume":"18","author":"Sleegers","year":"2016","journal-title":"Genet. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13024-017-0184-x","article-title":"Late onset Alzheimer\u2019s disease genetics implicates microglial pathways in disease risk","volume":"12","author":"Efthymiou","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s13024-015-0048-1","article-title":"Genetics ignite focus on microglial inflammation in Alzheimer\u2019s disease","volume":"10","author":"Malik","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.molmed.2017.03.008","article-title":"TREM2, microglia, and neurodegenerative diseases","volume":"23","author":"Yeh","year":"2017","journal-title":"Trends Mol. Med."},{"doi-asserted-by":"crossref","unstructured":"Su\u00e1rez-Calvet, M., Kleinberger, G., Caballero, M.\u00c1.A., Brendel, M., Rominger, A., Alcolea, D., Fortea, J., Lle\u00f3, A., Blesa, R., and Gispert, J.D. (2016). sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer\u2019s disease and associate with neuronal injury markers. EMBO Mol. Med., e201506123.","key":"ref_12","DOI":"10.15252\/emmm.201506123"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1007\/s00401-016-1533-5","article-title":"Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status","volume":"131","author":"Piccio","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.immuni.2017.08.015","article-title":"A tale of two genes: Microglial Apoe and Trem2","volume":"47","author":"Pimenova","year":"2017","journal-title":"Immunity"},{"doi-asserted-by":"crossref","unstructured":"Kober, D.L., Alexander-Brett, J.M., Karch, C.M., Cruchaga, C., Colonna, M., Holtzman, M.J., and Brett, T.J. (2016). Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife, 5.","key":"ref_15","DOI":"10.7554\/eLife.20391"},{"key":"ref_16","first-page":"369ra178","article-title":"Early changes in CSF sTREM2 in dominantly inherited Alzheimer\u2019s disease occur after amyloid deposition and neuronal injury","volume":"8","author":"Caballero","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/j.jalz.2016.06.005","article-title":"Cerebrospinal fluid sTREM2 levels are associated with gray matter volume increases and reduced diffusivity in early Alzheimer\u2019s disease","volume":"12","author":"Gispert","year":"2016","journal-title":"Alzheimer Dementia J. Alzheimer Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1056\/NEJMoa1211103","article-title":"Variant of TREM2 associated with the risk of Alzheimer\u2019s disease","volume":"368","author":"Jonsson","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1056\/NEJMoa1211851","article-title":"TREM2 variants in Alzheimer\u2019s disease","volume":"368","author":"Guerreiro","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-018-0298-9","article-title":"New insights into the role of TREM2 in Alzheimer\u2019s disease","volume":"13","author":"Gratuze","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-017-0197-5","article-title":"TREM2 in neurodegenerative diseases","volume":"12","author":"Jay","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"355","DOI":"10.3233\/JAD-161226","article-title":"Diagnostic biomarkers of Alzheimer\u2019s disease as identified in saliva using 1H nmR-based metabolomics","volume":"58","author":"Yilmaz","year":"2017","journal-title":"J. Alzheimer Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13024-016-0071-x","article-title":"Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer\u2019s disease","volume":"11","author":"Heslegrave","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1093\/brain\/awaa021","article-title":"Soluble TREM2 is elevated in Parkinson\u2019s disease subgroups with increased CSF tau","volume":"143","author":"Wilson","year":"2020","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1093\/brain\/awn217","article-title":"Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation","volume":"131","author":"Piccio","year":"2008","journal-title":"Brain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/wnan.84","article-title":"Magnetic nanoparticle biosensors","volume":"2","author":"Haun","year":"2010","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.snb.2006.11.042","article-title":"Carbon nanostructures as transducers in biosensors","volume":"126","author":"Vamvakaki","year":"2007","journal-title":"Sens. Actuators B Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nmat1508","article-title":"Single-quantum-dot-based DNA nanosensor","volume":"4","author":"Zhang","year":"2005","journal-title":"Nat. Mater."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/BF03214964","article-title":"Gold nanoparticle-based biosensors","volume":"43","author":"Li","year":"2010","journal-title":"Gold Bull."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1021\/nl203325s","article-title":"Nanoscale plasmonic interferometers for multispectral, high-throughput biochemical sensing","volume":"12","author":"Feng","year":"2012","journal-title":"Nano Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/nphoton.2012.45","article-title":"Sensing: Plasmonic interferometry","volume":"6","author":"Graydon","year":"2012","journal-title":"Nat. Photonics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"085021","DOI":"10.1088\/1367-2630\/15\/8\/085021","article-title":"Plasmonic and magnetoplasmonic interferometry for sensing","volume":"15","author":"Armelles","year":"2013","journal-title":"New J. Phys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"021104","DOI":"10.1063\/1.4775668","article-title":"Two-path solid-state interferometry using ultra-subwavelength two-dimensional plasmonic waves","volume":"102","author":"Yeung","year":"2013","journal-title":"Appl. Phys. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5859","DOI":"10.1364\/OE.21.005859","article-title":"Plasmonic interferometers for label-free multiplexed sensing","volume":"21","author":"Gao","year":"2013","journal-title":"Opt. Express"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4755","DOI":"10.1039\/c3lc50863c","article-title":"Plasmonic interferometric sensor arrays for high-performance label-free biomolecular detection","volume":"13","author":"Gao","year":"2013","journal-title":"Lab Chip"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20747","DOI":"10.1364\/OE.17.020747","article-title":"Vertical plasmonic Mach-Zehnder interferometer for sensitive optical sensing","volume":"17","author":"Gan","year":"2009","journal-title":"Opt. Express"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9836","DOI":"10.1021\/nn2034204","article-title":"Plasmonic Mach\u2013Zehnder interferometer for ultrasensitive on-chip biosensing","volume":"5","author":"Gao","year":"2011","journal-title":"ACS Nano"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20691","DOI":"10.1364\/OE.19.020691","article-title":"Non-spectroscopic refractometric nanosensor based on a tilted slit-groove plasmonic interferometer","volume":"19","author":"Li","year":"2011","journal-title":"Opt. Express"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1515\/nanoph-2013-0057","article-title":"A \u201cplasmonic cuvette\u201d: Dye chemistry coupled to plasmonic interferometry for glucose sensing","volume":"3","author":"Siu","year":"2014","journal-title":"Nanophotonics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e122","DOI":"10.1038\/lsa.2014.3","article-title":"Handheld high-throughput plasmonic biosensor using computational on-chip imaging","volume":"3","author":"Cetin","year":"2014","journal-title":"Light. Sci. Appl."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"25688","DOI":"10.1364\/OE.23.025688","article-title":"High-sensitivity liquid refractive-index sensor based on a Mach-Zehnder interferometer with a double-slot hybrid plasmonic waveguide","volume":"23","author":"Sun","year":"2015","journal-title":"Opt. Express"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"20836","DOI":"10.1038\/srep20836","article-title":"Nanoscale optical interferometry with incoherent light","volume":"6","author":"Li","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"27309","DOI":"10.1364\/OE.24.027309","article-title":"Higher-order surface plasmon contributions to passive and active plasmonic interferometry","volume":"24","author":"Li","year":"2016","journal-title":"Opt. Express"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1364\/OME.5.002742","article-title":"Circular slit-groove plasmonic interferometers: A generalized approach to high-throughput biochemical sensing","volume":"5","author":"Feng","year":"2015","journal-title":"Opt. Mater. Express"},{"doi-asserted-by":"crossref","unstructured":"Raether, H. (1988). Surface plasmons on smooth surfaces. Surface Plasmons on Smooth and Rough Surfaces and on Gratings, Springer.","key":"ref_45","DOI":"10.1007\/BFb0048317"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"083104","DOI":"10.1063\/1.4942013","article-title":"A spectroscopic refractometer based on plasmonic interferometry","volume":"119","author":"Feng","year":"2016","journal-title":"J. Appl. Phys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/nphoton.2016.162","article-title":"Measuring subwavelength spatial coherence with plasmonic interferometry","volume":"10","author":"Morrill","year":"2016","journal-title":"Nat. Photonics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4431","DOI":"10.1039\/c1an15325k","article-title":"Effect of antibody immobilization strategies on the analytical performance of a surface plasmon resonance-based immunoassay","volume":"136","author":"Vashist","year":"2011","journal-title":"Analyst"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6056","DOI":"10.1016\/j.apsusc.2012.02.137","article-title":"Immobilization of streptavidin on 4H\u2013SiC for biosensor development","volume":"258","author":"Williams","year":"2012","journal-title":"Appl. Surf. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.jim.2012.06.009","article-title":"Enzyme-linked immunosorbent assay (ELISA) and blocking with bovine serum albumin (BSA)\u2014not all BSAs are alike","volume":"384","author":"Xiao","year":"2012","journal-title":"J. Immunol. Methods"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/0952-7915(93)90019-O","article-title":"Surface plasmon resonance for detection and measurement of antibody-antigen affinity and kinetics","volume":"5","author":"Malmqvist","year":"1993","journal-title":"Curr. Opin. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1006\/abio.1993.1355","article-title":"Determination of rate and equilibrium binding constants for macromolecular interactions using surface plasmon resonance: Use of nonlinear least squares analysis methods","volume":"212","author":"Soneson","year":"1993","journal-title":"Anal. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0076-6879(94)40054-7","article-title":"Determination of rate and equilibrium binding constants for macromolecular interactions by surface plasmon resonance","volume":"Volume 240","author":"Soneson","year":"1994","journal-title":"Methods in Enzymology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0958-1669(05)80072-2","article-title":"Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: A critique of the surface plasmon resonance literature","volume":"5","year":"1994","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/S0958-1669(97)80157-7","article-title":"Kinetic analysis of macromolecular interactions using surface plasmon resonance biosensors","volume":"8","author":"Myszka","year":"1997","journal-title":"Curr. Opin. Biotechnol."},{"doi-asserted-by":"crossref","unstructured":"Cornish-Bowden, A. (2013). Fundamentals of Enzyme Kinetics, John Wiley & Sons.","key":"ref_56","DOI":"10.1016\/j.febslet.2013.06.009"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jcis.2008.05.052","article-title":"Quartz crystal microbalance study of protein adsorption kinetics on poly(2-hydroxyethyl methacrylate)","volume":"325","author":"Teichroeb","year":"2008","journal-title":"J. Colloid Interface Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1021\/la8031978","article-title":"Competitive Protein Adsorption\u2014Multilayer Adsorption and Surface Induced Protein Aggregation","volume":"25","author":"Holmberg","year":"2009","journal-title":"Langmuir"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0927-7765(99)00085-5","article-title":"Analysis of hen egg white lysozyme adsorption on Si (Ti) O2 aqueous solution interfaces at low ionic strength: A biphasic reaction related to solution self-association","volume":"17","author":"Ball","year":"2000","journal-title":"Colloids Surfaces B Biointerfaces"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/0927-7765(94)80066-9","article-title":"Globular proteins at solid\/liquid interfaces","volume":"2","author":"Haynes","year":"1994","journal-title":"Colloids Surfaces B Biointerfaces"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"13971","DOI":"10.1021\/jp804532v","article-title":"Surface Organization and Cooperativity during Nonspecific Protein Adsorption Events","volume":"112","author":"Rabe","year":"2008","journal-title":"J. Phys. Chem. B"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0301-4622(00)00151-4","article-title":"Effects of excluded surface area and adsorbate clustering on surface adsorption of proteins: I. Equilibrium models","volume":"86","author":"Minton","year":"2000","journal-title":"Biophys. Chem."}],"container-title":["Biosensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6374\/11\/7\/217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:24:45Z","timestamp":1760163885000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6374\/11\/7\/217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,1]]},"references-count":62,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["bios11070217"],"URL":"https:\/\/doi.org\/10.3390\/bios11070217","relation":{},"ISSN":["2079-6374"],"issn-type":[{"type":"electronic","value":"2079-6374"}],"subject":[],"published":{"date-parts":[[2021,7,1]]}}}