Blood-Based Biomarkers of Neuroinflammation in Alzheimer's Disease: A Central Role for Periphery?

Federica Angiulli, Elisa Conti, Chiara Paola Zoia, Fulvio Da Re, Ildebrando Appollonio, Carlo Ferrarese, Lucio Tremolizzo, Federica Angiulli, Elisa Conti, Chiara Paola Zoia, Fulvio Da Re, Ildebrando Appollonio, Carlo Ferrarese, Lucio Tremolizzo

Abstract

Neuroinflammation represents a central feature in the development of Alzheimer's disease (AD). The resident innate immune cells of the brain are the principal players in neuroinflammation, and their activation leads to a defensive response aimed at promoting β-amyloid (Aβ) clearance. However, it is now widely accepted that the peripheral immune system-by virtue of a dysfunctional blood-brain barrier (BBB)-is involved in the pathogenesis and progression of AD; microglial and astrocytic activation leads to the release of chemokines able to recruit peripheral immune cells into the central nervous system (CNS); at the same time, cytokines released by peripheral cells are able to cross the BBB and act upon glial cells, modifying their phenotype. To successfully fight this neurodegenerative disorder, accurate and sensitive biomarkers are required to be used for implementing an early diagnosis, monitoring the disease progression and treatment effectiveness. Interestingly, as a result of the bidirectional communication between the brain and the periphery, the blood compartment ends up reflecting several pathological changes occurring in the AD brain and can represent an accessible source for such biomarkers. In this review, we provide an overview on some of the most promising peripheral biomarkers of neuroinflammation, discussing their pathogenic role in AD.

Keywords: Alzheimer’s disease; TSPO; chemokines; cytokines; delirium; monocytes; neuroinflammation; peripheral markers.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(1) Beta-amyloid oligomers and their subsequent deposition in plaque fuel neuroinflammation, leading microglia to produce chemokines that lure monocytes into the brain. The chemotaxis process is regulated, among other players, by the TSPO, expressed by monocytes and well-known markers of activated microglia. (2) Besides entering the blood–brain barrier, peripheral monocytes produce proinflammatory cytokines that represent the afferent arm of the “inflammatory reflex”. (3) The efferent arm of this reflex is known as the “cholinergic anti-inflammatory pathway” (CAIP) and is represented by a vagal efflux indirectly stimulating the activation of the α7-nicotinic cholinergic receptor (α 7nAChR) expressed by peripheral monocytes and shutting off inflammasome and cytokine production. Created with BioRender.com.
Figure 2
Figure 2
(A) Mononucleate cells phagocytize beta-amyloid by TREM2 involvement (1). Due to the beta sheet-rich structure, the autophagy–lysosomal system (2) eventually results in incompetence for a full degradation and (3) leakage of the toxic peptide activates the inflammasome (4) with the secretion of proinflammatory cytokines (5), fueling downstream neuroinflammation. (B) In vitro phagocytosis assay; fluorescence micrograph showing beta-amyloid (in green) phagocytized by a THP-1 cell (acute monocytic leukemia line) (courtesy of Virginia Rodriguez-Menendez, UNIMIB, Italy). Created with BioRender.com.

References

    1. Hebert L.E., Bienias J.L., Aggarwal N.T., Wilson R.S., Bennett D.A., Shah R.C., Evans D.A. Change in risk of Alzheimer disease over time. Neurology. 2010;75:786–791. doi: 10.1212/WNL.0b013e3181f0754f.
    1. Armstrong R.A. What causes alzheimer’s disease? Folia Neuropathol. 2013;51:169–188. doi: 10.5114/fn.2013.37702.
    1. Carter J., Lippa C.F. Beta-amyloid, neuronal death and Alzheimer’s disease. Curr. Mol. Med. 2001;1:733–737. doi: 10.2174/1566524013363177.
    1. Zhang B., Gaiteri C., Bodea L.G., Wang Z., McElwee J., Podtelezhnikov A.A., Zhang C., Xie T., Tran L., Dobrin R., et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. 2013;153:707–720. doi: 10.1016/j.cell.2013.03.030.
    1. Heneka M.T., Carson M.J., El Khoury J., Landreth G.E., Brosseron F., Feinstein D.L., Jacobs A.H., Wyss-Coray T., Vitorica J., Ransohoff R.M., et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. doi: 10.1016/S1474-4422(15)70016-5.
    1. Kilimann I., Grothe M., Heinsen H., Alho E.J., Grinberg L., Amaro E., Dos Santos G.A., da Silva R.E., Mitchell A.J., Frisoni G.B., et al. Subregional basal forebrain atrophy in Alzheimer’s disease: A multicenter study. J. Alzheimers Dis. 2014;40:687–700. doi: 10.3233/JAD-132345.
    1. Selkoe D.J. Alzheimer’s disease is a synaptic failure. Science. 2002;298:789–791. doi: 10.1126/science.1074069.
    1. Arranz A.M., De Strooper B. The role of astroglia in Alzheimer’s disease: Pathophysiology and clinical implications. Lancet Neurol. 2019;18:406–414. doi: 10.1016/S1474-4422(18)30490-3.
    1. Klupp E., Grimmer T., Tahmasian M., Sorg C., Yakushev I., Yousefi B.H., Drzezga A., Förster S. Prefrontal hypometabolism in Alzheimer disease is related to longitudinal amyloid accumulation in remote brain regions. J. Nucl. Med. 2015;56:399–404. doi: 10.2967/jnumed.114.149302.
    1. Yamazaki Y., Kanekiyo T. Blood-Brain Barrier Dysfunction and the Pathogenesis of Alzheimer’s Disease. Int. J. Mol. Sci. 2017;18:1965. doi: 10.3390/ijms18091965.
    1. Tönnies E., Trushina E. Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease. J. Alzheimers Dis. 2017;57:1105–1121. doi: 10.3233/JAD-161088.
    1. Alzheimer A., Stelzmann R.A., Schnitzlein H.N., Murtagh F.R. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin. Anat. 1995;8:429–431. doi: 10.1002/ca.980080612.
    1. Hyman B.T., Phelps C.H., Beach T.G., Bigio E.H., Cairns N.J., Carrillo M.C., Dickson D.W., Duyckaerts C., Frosch M.P., Masliah E., et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012;8:1–13. doi: 10.1016/j.jalz.2011.10.007.
    1. McKhann G.M., Knopman D.S., Chertkow H., Hyman B.T., Jack C.R., Kawas C.H., Klunk W.E., Koroshetz W.J., Manly J.J., Mayeux R., et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–269. doi: 10.1016/j.jalz.2011.03.005.
    1. Jack C.R., Bennett D.A., Blennow K., Carrillo M.C., Dunn B., Haeberlein S.B., Holtzman D.M., Jagust W., Jessen F., Karlawish J., et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–562. doi: 10.1016/j.jalz.2018.02.018.
    1. Dubois B., Villain N., Frisoni G.B., Rabinovici G.D., Sabbagh M., Cappa S., Bejanin A., Bombois S., Epelbaum S., Teichmann M., et al. Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group. Lancet Neurol. 2021;20:484–496. doi: 10.1016/S1474-4422(21)00066-1.
    1. Morris J.C., Blennow K., Froelich L., Nordberg A., Soininen H., Waldemar G., Wahlund L.O., Dubois B. Harmonized diagnostic criteria for Alzheimer’s disease: Recommendations. J. Intern. Med. 2014;275:204–213. doi: 10.1111/joim.12199.
    1. Galimberti D., Scarpini E. Treatment of Alzheimer’s disease: Symptomatic and disease-modifying approaches. Curr. Aging Sci. 2010;3:46–56. doi: 10.2174/1874609811003010046.
    1. FDA-NIH Biomarker Working Group . BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet] Food and Drug Administration; Silve Spring, MD, USA: 2016.
    1. The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging Working Group Consensus report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer’s Disease”. Neurobiol. Aging. 1998;19:109–116.
    1. Brinker T., Stopa E., Morrison J., Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. 2014;11:10. doi: 10.1186/2045-8118-11-10.
    1. Wilkins J.M., Trushina E. Application of Metabolomics in Alzheimer’s Disease. Front. Neurol. 2017;8:719. doi: 10.3389/fneur.2017.00719.
    1. Ferreira D., Perestelo-Pérez L., Westman E., Wahlund L.O., Sarría A., Serrano-Aguilar P. Meta-Review of CSF Core Biomarkers in Alzheimer’s Disease: The State-of-the-Art after the New Revised Diagnostic Criteria. Front. Aging Neurosci. 2014;6:47. doi: 10.3389/fnagi.2014.00047.
    1. Hampel H., O’Bryant S.E., Molinuevo J.L., Zetterberg H., Masters C.L., Lista S., Kiddle S.J., Batrla R., Blennow K. Blood-based biomarkers for Alzheimer disease: Mapping the road to the clinic. Nat. Rev. Neurol. 2018;14:639–652. doi: 10.1038/s41582-018-0079-7.
    1. Zipser B.D., Johanson C.E., Gonzalez L., Berzin T.M., Tavares R., Hulette C.M., Vitek M.P., Hovanesian V., Stopa E.G. Microvascular injury and blood-brain barrier leakage in Alzheimer’s disease. Neurobiol. Aging. 2007;28:977–986. doi: 10.1016/j.neurobiolaging.2006.05.016.
    1. Thambisetty M., Lovestone S. Blood-based biomarkers of Alzheimer’s disease: Challenging but feasible. Biomark. Med. 2010;4:65–79. doi: 10.2217/bmm.09.84.
    1. Galasko D., Golde T.E. Biomarkers for Alzheimer’s disease in plasma, serum and blood—Conceptual and practical problems. Alzheimers Res. Ther. 2013;5:10. doi: 10.1186/alzrt164.
    1. Serrano-Pozo A., Mielke M.L., Gómez-Isla T., Betensky R.A., Growdon J.H., Frosch M.P., Hyman B.T. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am. J. Pathol. 2011;179:1373–1384. doi: 10.1016/j.ajpath.2011.05.047.
    1. Nimmerjahn A., Kirchhoff F., Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–1318. doi: 10.1126/science.1110647.
    1. Bamberger M.E., Harris M.E., McDonald D.R., Husemann J., Landreth G.E. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J. Neurosci. 2003;23:2665–2674. doi: 10.1523/JNEUROSCI.23-07-02665.2003.
    1. Michelucci A., Heurtaux T., Grandbarbe L., Morga E., Heuschling P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta. J. Neuroimmunol. 2009;210:3–12. doi: 10.1016/j.jneuroim.2009.02.003.
    1. Czeh M., Gressens P., Kaindl A.M. The yin and yang of microglia. Dev. Neurosci. 2011;33:199–209. doi: 10.1159/000328989.
    1. Bolmont T., Haiss F., Eicke D., Radde R., Mathis C.A., Klunk W.E., Kohsaka S., Jucker M., Calhoun M.E. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J. Neurosci. 2008;28:4283–4292. doi: 10.1523/JNEUROSCI.4814-07.2008.
    1. Hickman S.E., Allison E.K., El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci. 2008;28:8354–8360. doi: 10.1523/JNEUROSCI.0616-08.2008.
    1. Sheng J.G., Zhou X.Q., Mrak R.E., Griffin W.S. Progressive neuronal injury associated with amyloid plaque formation in Alzheimer disease. J. Neuropathol. Exp. Neurol. 1998;57:714–717. doi: 10.1097/00005072-199807000-00008.
    1. Frank-Cannon T.C., Alto L.T., McAlpine F.E., Tansey M.G. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol. Neurodegener. 2009;4:47. doi: 10.1186/1750-1326-4-47.
    1. Sofroniew M.V., Vinters H.V. Astrocytes: Biology and pathology. Acta Neuropathol. 2010;119:7–35. doi: 10.1007/s00401-009-0619-8.
    1. Abbott N.J., Rönnbäck L., Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 2006;7:41–53. doi: 10.1038/nrn1824.
    1. Wisniewski H.M., Wegiel J. Spatial relationships between astrocytes and classical plaque components. Neurobiol. Aging. 1991;12:593–600. doi: 10.1016/0197-4580(91)90091-W.
    1. Orre M., Kamphuis W., Osborn L.M., Jansen A.H.P., Kooijman L., Bossers K., Hol E.M. Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol. Aging. 2014;35:2746–2760. doi: 10.1016/j.neurobiolaging.2014.06.004.
    1. Rolyan H., Feike A.C., Upadhaya A.R., Waha A., Van Dooren T., Haass C., Birkenmeier G., Pietrzik C.U., Van Leuven F., Thal D.R. Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer’s disease. J. Neural. Transm. 2011;118:699–712. doi: 10.1007/s00702-010-0572-7.
    1. Wyss-Coray T., Loike J.D., Brionne T.C., Lu E., Anankov R., Yan F., Silverstein S.C., Husemann J. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat. Med. 2003;9:453–457. doi: 10.1038/nm838.
    1. Hu J., Akama K.T., Krafft G.A., Chromy B.A., Van Eldik L.J. Amyloid-beta peptide activates cultured astrocytes: Morphological alterations, cytokine induction and nitric oxide release. Brain Res. 1998;785:195–206. doi: 10.1016/S0006-8993(97)01318-8.
    1. Von Bernhardi R., Eugenín J. Microglial reactivity to beta-amyloid is modulated by astrocytes and proinflammatory factors. Brain Res. 2004;1025:186–193. doi: 10.1016/j.brainres.2004.07.084.
    1. Yang J., Lunde L.K., Nuntagij P., Oguchi T., Camassa L.M., Nilsson L.N., Lannfelt L., Xu Y., Amiry-Moghaddam M., Ottersen O.P., et al. Loss of astrocyte polarization in the tg-ArcSwe mouse model of Alzheimer’s disease. J. Alzheimers Dis. 2011;27:711–722. doi: 10.3233/JAD-2011-110725.
    1. Iram T., Trudler D., Kain D., Kanner S., Galron R., Vassar R., Barzilai A., Blinder P., Fishelson Z., Frenkel D. Astrocytes from old Alzheimer’s disease mice are impaired in Aβ uptake and in neuroprotection. Neurobiol. Dis. 2016;96:84–94. doi: 10.1016/j.nbd.2016.08.001.
    1. Zenaro E., Piacentino G., Constantin G. The blood-brain barrier in Alzheimer’s disease. Neurobiol. Dis. 2017;107:41–56. doi: 10.1016/j.nbd.2016.07.007.
    1. Procter T.V., Williams A., Montagne A. Interplay between brain pericytes and endothelial cells in dementia. Am. J. Pathol. 2021 doi: 10.1016/j.ajpath.2021.07.003.
    1. Anwar M.M., Özkan E., Gürsoy-Özdemir Y. The role of extracellular matrix alterations in mediating astrocyte damage and pericyte dysfunction in Alzheimer’s disease: A comprehensive review. Eur. J. Neurosci. 2021 doi: 10.1111/ejn.15372.
    1. Sengillo J.D., Winkler E.A., Walker C.T., Sullivan J.S., Johnson M., Zlokovic B.V. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer’s disease. Brain Pathol. 2013;23:303–310. doi: 10.1111/bpa.12004.
    1. Montagne A., Barnes S.R., Sweeney M.D., Halliday M.R., Sagare A.P., Zhao Z., Toga A.W., Jacobs R.E., Liu C.Y., Amezcua L., et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85:296–302. doi: 10.1016/j.neuron.2014.12.032.
    1. Montagne A., Nation D.A., Sagare A.P., Barisano G., Sweeney M.D., Chakhoyan A., Pachicano M., Joe E., Nelson A.R., D’Orazio L.M., et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020;581:71–76. doi: 10.1038/s41586-020-2247-3.
    1. Cai Z., Xiao M. Oligodendrocytes and Alzheimer’s disease. Int. J. Neurosci. 2016;126:97–104. doi: 10.3109/00207454.2015.1025778.
    1. Nihonmatsu-Kikuchi N., Yu X.J., Matsuda Y., Ozawa N., Ito T., Satou K., Kaname T., Iwasaki Y., Akagi A., Yoshida M., et al. Essential roles of plexin-B3. Commun. Biol. 2021;4:870. doi: 10.1038/s42003-021-02404-7.
    1. Daneman R., Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7:a020412. doi: 10.1101/cshperspect.a020412.
    1. Wong D., Dorovini-Zis K., Vincent S.R. Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier. Exp. Neurol. 2004;190:446–455. doi: 10.1016/j.expneurol.2004.08.008.
    1. Van Wetering S., van Buul J.D., Quik S., Mul F.P., Anthony E.C., ten Klooster J.P., Collard J.G., Hordijk P.L. Reactive oxygen species mediate Rac-induced loss of cell-cell adhesion in primary human endothelial cells. J. Cell Sci. 2002;115:1837–1846. doi: 10.1242/jcs.115.9.1837.
    1. Gurney K.J., Estrada E.Y., Rosenberg G.A. Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation. Neurobiol. Dis. 2006;23:87–96. doi: 10.1016/j.nbd.2006.02.006.
    1. Vinters H.V. Cerebral amyloid angiopathy. A critical review. Stroke. 1987;18:311–324. doi: 10.1161/01.STR.18.2.311.
    1. Fiala M., Zhang L., Gan X., Sherry B., Taub D., Graves M.C., Hama S., Way D., Weinand M., Witte M., et al. Amyloid-beta induces chemokine secretion and monocyte migration across a human blood–brain barrier model. Mol. Med. 1998;4:480–489. doi: 10.1007/BF03401753.
    1. Krstic D., Madhusudan A., Doehner J., Vogel P., Notter T., Imhof C., Manalastas A., Hilfiker M., Pfister S., Schwerdel C., et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J. Neuroinflamm. 2012;9:151. doi: 10.1186/1742-2094-9-151.
    1. Ishizuka K., Kimura T., Igata-yi R., Katsuragi S., Takamatsu J., Miyakawa T. Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer’s disease. Psychiatry Clin. Neurosci. 1997;51:135–138. doi: 10.1111/j.1440-1819.1997.tb02375.x.
    1. Simard A.R., Soulet D., Gowing G., Julien J.P., Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron. 2006;49:489–502. doi: 10.1016/j.neuron.2006.01.022.
    1. Ferrarese C., Appollonio I., Frigo M., Perego M., Pierpaoli C., Trabucchi M., Frattola L. Characterization of peripheral benzodiazepine receptors in human blood mononuclear cells. Neuropharmacology. 1990;29:375–378. doi: 10.1016/0028-3908(90)90097-B.
    1. Sacerdote P., Locatelli L.D., Panerai A.E. Benzodiazepine induced chemotaxis of human monocytes: A tool for the study of benzodiazepine receptors. Life Sci. 1993;53:653–658. doi: 10.1016/0024-3205(93)90275-8.
    1. Stalder A.K., Ermini F., Bondolfi L., Krenger W., Burbach G.J., Deller T., Coomaraswamy J., Staufenbiel M., Landmann R., Jucker M. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci. 2005;25:11125–11132. doi: 10.1523/JNEUROSCI.2545-05.2005.
    1. Michaud J.P., Bellavance M.A., Préfontaine P., Rivest S. Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep. 2013;5:646–653. doi: 10.1016/j.celrep.2013.10.010.
    1. Fiala M., Lin J., Ringman J., Kermani-Arab V., Tsao G., Patel A., Lossinsky A.S., Graves M.C., Gustavson A., Sayre J., et al. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J. Alzheimers Dis. 2005;7:221–232. doi: 10.3233/JAD-2005-7304. discussion 255–262.
    1. Marsh S.E., Abud E.M., Lakatos A., Karimzadeh A., Yeung S.T., Davtyan H., Fote G.M., Lau L., Weinger J.G., Lane T.E., et al. The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc. Natl. Acad. Sci. USA. 2016;113:E1316–E1325. doi: 10.1073/pnas.1525466113.
    1. Togo T., Akiyama H., Iseki E., Kondo H., Ikeda K., Kato M., Oda T., Tsuchiya K., Kosaka K. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J. Neuroimmunol. 2002;124:83–92. doi: 10.1016/S0165-5728(01)00496-9.
    1. Lueg G., Gross C.C., Lohmann H., Johnen A., Kemmling A., Deppe M., Groger J., Minnerup J., Wiendl H., Meuth S.G., et al. Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer’s disease. Neurobiol. Aging. 2015;36:81–89. doi: 10.1016/j.neurobiolaging.2014.08.008.
    1. Söllvander S., Ekholm-Pettersson F., Brundin R.M., Westman G., Kilander L., Paulie S., Lannfelt L., Sehlin D. Increased Number of Plasma B Cells Producing Autoantibodies Against Aβ42 Protofibrils in Alzheimer’s Disease. J. Alzheimers Dis. 2015;48:63–72. doi: 10.3233/JAD-150236.
    1. Town T., Tan J., Flavell R.A., Mullan M. T-cells in Alzheimer’s disease. Neuromol. Med. 2005;7:255–264. doi: 10.1385/NMM:7:3:255.
    1. Lue L.F., Walker D.G. Modeling Alzheimer’s disease immune therapy mechanisms: Interactions of human postmortem microglia with antibody-opsonized amyloid beta peptide. J. Neurosci. Res. 2002;70:599–610. doi: 10.1002/jnr.10422.
    1. Deane R., Sagare A., Hamm K., Parisi M., LaRue B., Guo H., Wu Z., Holtzman D.M., Zlokovic B.V. IgG-assisted age-dependent clearance of Alzheimer’s amyloid beta peptide by the blood-brain barrier neonatal Fc receptor. J. Neurosci. 2005;25:11495–11503. doi: 10.1523/JNEUROSCI.3697-05.2005.
    1. DeMattos R.B., Bales K.R., Cummins D.J., Dodart J.C., Paul S.M., Holtzman D.M. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. 2001;98:8850–8855. doi: 10.1073/pnas.151261398.
    1. Lafaye P., Achour I., England P., Duyckaerts C., Rougeon F. Single-domain antibodies recognize selectively small oligomeric forms of amyloid beta, prevent Abeta-induced neurotoxicity and inhibit fibril formation. Mol. Immunol. 2009;46:695–704. doi: 10.1016/j.molimm.2008.09.008.
    1. Conti E., Tremolizzo L., Santarone M.E., Tironi M., Radice I., Zoia C.P., Aliprandi A., Salmaggi A., Dominici R., Casati M., et al. Donepezil modulates the endogenous immune response: Implications for Alzheimer’s disease. Hum. Psychopharmacol. 2016;31:296–303. doi: 10.1002/hup.2538.
    1. Banks W.A., Kastin A.J., Broadwell R.D. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation. 1995;2:241–248. doi: 10.1159/000097202.
    1. Watkins L.R., Goehler L.E., Relton J.K., Tartaglia N., Silbert L., Martin D., Maier S.F. Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: Evidence for vagal mediation of immune-brain communication. Neurosci. Lett. 1995;183:27–31. doi: 10.1016/0304-3940(94)11105-R.
    1. Hoogland I.C., Houbolt C., van Westerloo D.J., van Gool W.A., van de Beek D. Systemic inflammation and microglial activation: Systematic review of animal experiments. J. Neuroinflamm. 2015;12:114. doi: 10.1186/s12974-015-0332-6.
    1. Scassellati C., Galoforo A.C., Esposito C., Ciani M., Ricevuti G., Bonvicini C. Promising Intervention Approaches to Potentially Resolve Neuroinflammation And Steroid Hormones Alterations in Alzheimer’s Disease and Its Neuropsychiatric Symptoms. Aging Dis. 2021;12:1337–1357. doi: 10.14336/AD.2021.0122.
    1. Sharma V.K., Singh T.G., Garg N., Dhiman S., Gupta S., Rahman M.H., Najda A., Walasek-Janusz M., Kamel M., Albadrani G.M., et al. Dysbiosis and Alzheimer’s Disease: A Role for Chronic Stress? Biomolecules. 2021;11:678. doi: 10.3390/biom11050678.
    1. Zheng D., Liwinski T., Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020;30:492–506. doi: 10.1038/s41422-020-0332-7.
    1. Van Olst L., Roks S.J.M., Kamermans A., Verhaar B.J.H., van der Geest A.M., Muller M., van der Flier W.M., de Vries H.E. Contribution of Gut Microbiota to Immunological Changes in Alzheimer’s Disease. Front. Immunol. 2021;12:683068. doi: 10.3389/fimmu.2021.683068.
    1. Kim M.S., Kim Y., Choi H., Kim W., Park S., Lee D., Kim D.K., Kim H.J., Hyun D.W., Lee J.Y., et al. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut. 2020;69:283–294. doi: 10.1136/gutjnl-2018-317431.
    1. Franceschi C., Capri M., Monti D., Giunta S., Olivieri F., Sevini F., Panourgia M.P., Invidia L., Celani L., Scurti M., et al. Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 2007;128:92–105. doi: 10.1016/j.mad.2006.11.016.
    1. Norden D.M., Godbout J.P. Review: Microglia of the aged brain: Primed to be activated and resistant to regulation. Neuropathol. Appl. Neurobiol. 2013;39:19–34. doi: 10.1111/j.1365-2990.2012.01306.x.
    1. Nordengen K., Kirsebom B.E., Henjum K., Selnes P., Gísladóttir B., Wettergreen M., Torsetnes S.B., Grøntvedt G.R., Waterloo K.K., Aarsland D., et al. Glial activation and inflammation along the Alzheimer’s disease continuum. J. Neuroinflamm. 2019;16:46. doi: 10.1186/s12974-019-1399-2.
    1. Konsman J.P., Parnet P., Dantzer R. Cytokine-induced sickness behaviour: Mechanisms and implications. Trends Neurosci. 2002;25:154–159. doi: 10.1016/S0166-2236(00)02088-9.
    1. Maldonado J.R. Acute Brain Failure: Pathophysiology, Diagnosis, Management, and Sequelae of Delirium. Crit. Care Clin. 2017;33:461–519. doi: 10.1016/j.ccc.2017.03.013.
    1. Murray C., Sanderson D.J., Barkus C., Deacon R.M., Rawlins J.N., Bannerman D.M., Cunningham C. Systemic inflammation induces acute working memory deficits in the primed brain: Relevance for delirium. Neurobiol. Aging. 2012;33:603.e3–616.e3. doi: 10.1016/j.neurobiolaging.2010.04.002.
    1. Elie M., Cole M.G., Primeau F.J., Bellavance F. Delirium risk factors in elderly hospitalized patients. J. Gen. Intern. Med. 1998;13:204–212. doi: 10.1046/j.1525-1497.1998.00047.x.
    1. Bugiani O. Why is delirium more frequent in the elderly? Neurol. Sci. 2021;42:3491–3503. doi: 10.1007/s10072-021-05339-3.
    1. Fong T.G., Jones R.N., Shi P., Marcantonio E.R., Yap L., Rudolph J.L., Yang F.M., Kiely D.K., Inouye S.K. Delirium accelerates cognitive decline in Alzheimer disease. Neurology. 2009;72:1570–1575. doi: 10.1212/WNL.0b013e3181a4129a.
    1. Eikelenboom P., Hoogendijk W.J. Do delirium and Alzheimer’s dementia share specific pathogenetic mechanisms? Dement. Geriatr. Cogn. Disord. 1999;10:319–324. doi: 10.1159/000017162.
    1. Tracey K.J. The inflammatory reflex. Nature. 2002;420:853–859. doi: 10.1038/nature01321.
    1. Wang H., Yu M., Ochani M., Amella C.A., Tanovic M., Susarla S., Li J.H., Yang H., Ulloa L., Al-Abed Y., et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384–388. doi: 10.1038/nature01339.
    1. Patel N.S., Paris D., Mathura V., Quadros A.N., Crawford F.C., Mullan M.J. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J. Neuroinflamm. 2005;2:9. doi: 10.1186/1742-2094-2-9.
    1. Arango Duque G., Descoteaux A. Macrophage cytokines: Involvement in immunity and infectious diseases. Front. Immunol. 2014;5:491. doi: 10.3389/fimmu.2014.00491.
    1. Wu Y.Y., Hsu J.L., Wang H.C., Wu S.J., Hong C.J., Cheng I.H. Alterations of the Neuroinflammatory Markers IL-6 and TRAIL in Alzheimer’s Disease. Dement. Geriatr. Cogn. Dis. Extra. 2015;5:424–434. doi: 10.1159/000439214.
    1. Forlenza O.V., Diniz B.S., Talib L.L., Mendonça V.A., Ojopi E.B., Gattaz W.F., Teixeira A.L. Increased serum IL-1beta level in Alzheimer’s disease and mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 2009;28:507–512. doi: 10.1159/000255051.
    1. Fillit H., Ding W.H., Buee L., Kalman J., Altstiel L., Lawlor B., Wolf-Klein G. Elevated circulating tumor necrosis factor levels in Alzheimer’s disease. Neurosci. Lett. 1991;129:318–320. doi: 10.1016/0304-3940(91)90490-K.
    1. Alvarez A., Cacabelos R., Sanpedro C., García-Fantini M., Aleixandre M. Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol. Aging. 2007;28:533–536. doi: 10.1016/j.neurobiolaging.2006.02.012.
    1. Van Duijn C.M., Hofman A., Nagelkerken L. Serum levels of interleukin-6 are not elevated in patients with Alzheimer’s disease. Neurosci. Lett. 1990;108:350–354. doi: 10.1016/0304-3940(90)90666-W.
    1. Pirttila T., Mehta P.D., Frey H., Wisniewski H.M. Alpha 1-antichymotrypsin and IL-1 beta are not increased in CSF or serum in Alzheimer’s disease. Neurobiol. Aging. 1994;15:313–317. doi: 10.1016/0197-4580(94)90026-4.
    1. Yasutake C., Kuroda K., Yanagawa T., Okamura T., Yoneda H. Serum BDNF, TNF-alpha and IL-1beta levels in dementia patients: Comparison between Alzheimer’s disease and vascular dementia. Eur. Arch. Psychiatry Clin. Neurosci. 2006;256:402–406. doi: 10.1007/s00406-006-0652-8.
    1. Bermejo P., Martín-Aragón S., Benedí J., Susín C., Felici E., Gil P., Ribera J.M., Villar A.M. Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer’s disease. Immunol. Lett. 2008;117:198–202. doi: 10.1016/j.imlet.2008.02.002.
    1. Paganelli R., Di Iorio A., Patricelli L., Ripani F., Sparvieri E., Faricelli R., Iarlori C., Porreca E., Di Gioacchino M., Abate G. Proinflammatory cytokines in sera of elderly patients with dementia: Levels in vascular injury are higher than those of mild-moderate Alzheimer’s disease patients. Exp. Gerontol. 2002;37:257–263. doi: 10.1016/S0531-5565(01)00191-7.
    1. Sun Y.X., Minthon L., Wallmark A., Warkentin S., Blennow K., Janciauskiene S. Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 2003;16:136–144. doi: 10.1159/000071001.
    1. Fiorentino D.F., Zlotnik A., Mosmann T.R., Howard M., O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J. Immunol. 1991;147:3815–3822.
    1. Stein M., Keshav S., Harris N., Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: A marker of alternative immunologic macrophage activation. J. Exp. Med. 1992;176:287–292. doi: 10.1084/jem.176.1.287.
    1. Te Velde A.A., Huijbens R.J., Heije K., de Vries J.E., Figdor C.G. Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes. Blood. 1990;76:1392–1397. doi: 10.1182/blood.V76.7.1392.1392.
    1. Gong D., Shi W., Yi S.J., Chen H., Groffen J., Heisterkamp N. TGFβ signaling plays a critical role in promoting alternative macrophage activation. BMC Immunol. 2012;13:31. doi: 10.1186/1471-2172-13-31.
    1. Rousset F., Garcia E., Defrance T., Péronne C., Vezzio N., Hsu D.H., Kastelein R., Moore K.W., Banchereau J. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc. Natl. Acad. Sci. USA. 1992;89:1890–1893. doi: 10.1073/pnas.89.5.1890.
    1. Hsieh C.S., Heimberger A.B., Gold J.S., O’Garra A., Murphy K.M. Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system. Proc. Natl. Acad. Sci. USA. 1992;89:6065–6069. doi: 10.1073/pnas.89.13.6065.
    1. Defrance T., Vanbervliet B., Brière F., Durand I., Rousset F., Banchereau J. Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J. Exp. Med. 1992;175:671–682. doi: 10.1084/jem.175.3.671.
    1. Ledeboer A., Brevé J.J., Poole S., Tilders F.J., Van Dam A.M. Interleukin-10, interleukin-4, and transforming growth factor-beta differentially regulate lipopolysaccharide-induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells. Glia. 2000;30:134–142. doi: 10.1002/(SICI)1098-1136(200004)30:2<134::AID-GLIA3>;2-3.
    1. Garg S.K., Kipnis J., Banerjee R. IFN-gamma and IL-4 differentially shape metabolic responses and neuroprotective phenotype of astrocytes. J. Neurochem. 2009;108:1155–1166. doi: 10.1111/j.1471-4159.2009.05872.x.
    1. Shimizu E., Kawahara K., Kajizono M., Sawada M., Nakayama H. IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1-42) by rat primary type 2 microglia. J. Immunol. 2008;181:6503–6513. doi: 10.4049/jimmunol.181.9.6503.
    1. Derecki N.C., Cardani A.N., Yang C.H., Quinnies K.M., Crihfield A., Lynch K.R., Kipnis J. Regulation of learning and memory by meningeal immunity: A key role for IL-4. J. Exp. Med. 2010;207:1067–1080. doi: 10.1084/jem.20091419.
    1. Wyss-Coray T., Lin C., Yan F., Yu G.Q., Rohde M., McConlogue L., Masliah E., Mucke L. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat. Med. 2001;7:612–618. doi: 10.1038/87945.
    1. Bonotis K., Krikki E., Holeva V., Aggouridaki C., Costa V., Baloyannis S. Systemic immune aberrations in Alzheimer’s disease patients. J. Neuroimmunol. 2008;193:183–187. doi: 10.1016/j.jneuroim.2007.10.020.
    1. Swardfager W., Lanctôt K., Rothenburg L., Wong A., Cappell J., Herrmann N. A meta-analysis of cytokines in Alzheimer’s disease. Biol. Psychiatry. 2010;68:930–941. doi: 10.1016/j.biopsych.2010.06.012.
    1. Choi C., Jeong J.H., Jang J.S., Choi K., Lee J., Kwon J., Choi K.G., Lee J.S., Kang S.W. Multiplex analysis of cytokines in the serum and cerebrospinal fluid of patients with Alzheimer’s disease by color-coded bead technology. J. Clin. Neurol. 2008;4:84–88. doi: 10.3988/jcn.2008.4.2.84.
    1. Malaguarnera L., Motta M., Di Rosa M., Anzaldi M., Malaguarnera M. Interleukin-18 and transforming growth factor-beta 1 plasma levels in Alzheimer’s disease and vascular dementia. Neuropathology. 2006;26:307–312. doi: 10.1111/j.1440-1789.2006.00701.x.
    1. Anuradha U., Kumar A., Singh R.K. The clinical correlation of proinflammatory and anti-inflammatory biomarkers with Alzheimer disease: A meta-analysis. Neurol. Sci. 2021 doi: 10.1007/s10072-021-05343-7. in press.
    1. Motta M., Imbesi R., Di Rosa M., Stivala F., Malaguarnera L. Altered plasma cytokine levels in Alzheimer’s disease: Correlation with the disease progression. Immunol. Lett. 2007;114:46–51. doi: 10.1016/j.imlet.2007.09.002.
    1. Xia M., Qin S., McNamara M., Mackay C., Hyman B.T. Interleukin-8 receptor B immunoreactivity in brain and neuritic plaques of Alzheimer’s disease. Am. J. Pathol. 1997;150:1267–1274.
    1. Meda L., Bernasconi S., Bonaiuto C., Sozzani S., Zhou D., Otvos L., Mantovani A., Rossi F., Cassatella M.A. Beta-amyloid (25-35) peptide and IFN-gamma synergistically induce the production of the chemotactic cytokine MCP-1/JE in monocytes and microglial cells. J. Immunol. 1996;157:1213–1218.
    1. Johnstone M., Gearing A.J., Miller K.M. A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J. Neuroimmunol. 1999;93:182–193. doi: 10.1016/S0165-5728(98)00226-4.
    1. Peterson P.K., Hu S., Salak-Johnson J., Molitor T.W., Chao C.C. Differential production of and migratory response to beta chemokines by human microglia and astrocytes. J. Infect. Dis. 1997;175:478–481. doi: 10.1093/infdis/175.2.478.
    1. Kiyota T., Gendelman H.E., Weir R.A., Higgins E.E., Zhang G., Jain M. CCL2 affects β-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer’s disease. Neurobiol. Aging. 2013;34:1060–1068. doi: 10.1016/j.neurobiolaging.2012.08.009.
    1. Sokolova A., Hill M.D., Rahimi F., Warden L.A., Halliday G.M., Shepherd C.E. Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer’s disease. Brain Pathol. 2009;19:392–398. doi: 10.1111/j.1750-3639.2008.00188.x.
    1. Kim S.M., Song J., Kim S., Han C., Park M.H., Koh Y., Jo S.A., Kim Y.Y. Identification of peripheral inflammatory markers between normal control and Alzheimer’s disease. BMC Neurol. 2011;11:51. doi: 10.1186/1471-2377-11-51.
    1. Corrêa J.D., Starling D., Teixeira A.L., Caramelli P., Silva T.A. Chemokines in CSF of Alzheimer’s disease patients. Arq. Neuropsiquiatr. 2011;69:455–459. doi: 10.1590/S0004-282X2011000400009.
    1. Galimberti D., Fenoglio C., Lovati C., Venturelli E., Guidi I., Corrà B., Scalabrini D., Clerici F., Mariani C., Bresolin N., et al. Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer’s disease. Neurobiol. Aging. 2006;27:1763–1768. doi: 10.1016/j.neurobiolaging.2005.10.007.
    1. Ehrlich L.C., Hu S., Sheng W.S., Sutton R.L., Rockswold G.L., Peterson P.K., Chao C.C. Cytokine regulation of human microglial cell IL-8 production. J. Immunol. 1998;160:1944–1948.
    1. Meda L., Bonaiuto C., Szendrei G.I., Ceska M., Rossi F., Cassatella M.A. beta-Amyloid(25-35) induces the production of interleukin-8 from human monocytes. J. Neuroimmunol. 1995;59:29–33. doi: 10.1016/0165-5728(95)00021-S.
    1. Alsadany M.A., Shehata H.H., Mohamad M.I., Mahfouz R.G. Histone deacetylases enzyme, copper, and IL-8 levels in patients with Alzheimer’s disease. Am. J. Alzheimers Dis. Other Dement. 2013;28:54–61. doi: 10.1177/1533317512467680.
    1. Galimberti D., Schoonenboom N., Scheltens P., Fenoglio C., Bouwman F., Venturelli E., Guidi I., Blankenstein M.A., Bresolin N., Scarpini E. Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch. Neurol. 2006;63:538–543. doi: 10.1001/archneur.63.4.538.
    1. Detmers P.A., Lo S.K., Olsen-Egbert E., Walz A., Baggiolini M., Cohn Z.A. Neutrophil-activating protein 1/interleukin 8 stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human neutrophils. J. Exp. Med. 1990;171:1155–1162. doi: 10.1084/jem.171.4.1155.
    1. Liu Y.J., Guo D.W., Tian L., Shang D.S., Zhao W.D., Li B., Fang W.G., Zhu L., Chen Y.H. Peripheral T cells derived from Alzheimer’s disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-alpha-dependent. Neurobiol. Aging. 2010;31:175–188. doi: 10.1016/j.neurobiolaging.2008.03.024.
    1. Ashutosh, Kou W., Cotter R., Borgmann K., Wu L., Persidsky R., Sakhuja N., Ghorpade A. CXCL8 protects human neurons from amyloid-β-induced neurotoxicity: Relevance to Alzheimer’s disease. Biochem. Biophys. Res. Commun. 2011;412:565–571. doi: 10.1016/j.bbrc.2011.07.127.
    1. Huang D., Shi F.D., Jung S., Pien G.C., Wang J., Salazar-Mather T.P., He T.T., Weaver J.T., Ljunggren H.G., Biron C.A., et al. The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system. FASEB J. 2006;20:896–905. doi: 10.1096/fj.05-5465com.
    1. Zujovic V., Benavides J., Vigé X., Carter C., Taupin V. Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia. 2000;29:305–315. doi: 10.1002/(SICI)1098-1136(20000215)29:4<305::AID-GLIA2>;2-V.
    1. Perea J.R., Lleó A., Alcolea D., Fortea J., Ávila J., Bolós M. Decreased CX3CL1 Levels in the Cerebrospinal Fluid of Patients With Alzheimer’s Disease. Front. Neurosci. 2018;12:609. doi: 10.3389/fnins.2018.00609.
    1. Kim T.S., Lim H.K., Lee J.Y., Kim D.J., Park S., Lee C., Lee C.U. Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci. Lett. 2008;436:196–200. doi: 10.1016/j.neulet.2008.03.019.
    1. Rejman J.J., Hurley W.L. Isolation and characterization of a novel 39 kilodalton whey protein from bovine mammary secretions collected during the nonlactating period. Biochem. Biophys. Res. Commun. 1988;150:329–334. doi: 10.1016/0006-291X(88)90524-4.
    1. Yeo I.J., Lee C.K., Han S.B., Yun J., Hong J.T. Roles of chitinase 3-like 1 in the development of cancer, neurodegenerative diseases, and inflammatory diseases. Pharmacol. Ther. 2019;203:107394. doi: 10.1016/j.pharmthera.2019.107394.
    1. Bonneh-Barkay D., Bissel S.J., Kofler J., Starkey A., Wang G., Wiley C.A. Astrocyte and macrophage regulation of YKL-40 expression and cellular response in neuroinflammation. Brain Pathol. 2012;22:530–546. doi: 10.1111/j.1750-3639.2011.00550.x.
    1. Rehli M., Niller H.H., Ammon C., Langmann S., Schwarzfischer L., Andreesen R., Krause S.W. Transcriptional regulation of CHI3L1, a marker gene for late stages of macrophage differentiation. J. Biol. Chem. 2003;278:44058–44067. doi: 10.1074/jbc.M306792200.
    1. Xu N., Bo Q., Shao R., Liang J., Zhai Y., Yang S., Wang F., Sun X. Chitinase-3-Like-1 Promotes M2 Macrophage Differentiation and Induces Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2019;60:4596–4605. doi: 10.1167/iovs.19-27493.
    1. Bonneh-Barkay D., Wang G., Starkey A., Hamilton R.L., Wiley C.A. In vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases. J. Neuroinflamm. 2010;7:34. doi: 10.1186/1742-2094-7-34.
    1. Craig-Schapiro R., Perrin R.J., Roe C.M., Xiong C., Carter D., Cairns N.J., Mintun M.A., Peskind E.R., Li G., Galasko D.R., et al. YKL-40: A novel prognostic fluid biomarker for preclinical Alzheimer’s disease. Biol. Psychiatry. 2010;68:903–912. doi: 10.1016/j.biopsych.2010.08.025.
    1. Llorens F., Thüne K., Tahir W., Kanata E., Diaz-Lucena D., Xanthopoulos K., Kovatsi E., Pleschka C., Garcia-Esparcia P., Schmitz M., et al. YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias. Mol. Neurodegener. 2017;12:83. doi: 10.1186/s13024-017-0226-4.
    1. Choi J.Y., Yeo I.J., Kim K.C., Choi W.R., Jung J.K., Han S.B., Hong J.T. K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression. J. Neuroinflamm. 2018;15:224. doi: 10.1186/s12974-018-1269-3.
    1. Lananna B.V., McKee C.A., King M.W., Del-Aguila J.L., Dimitry J.M., Farias F.H.G., Nadarajah C.J., Xiong D.D., Guo C., Cammack A.J., et al. Chi3l1 /YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer’s disease pathogenesis. Sci. Transl. Med. 2020;12:eaax3519. doi: 10.1126/scitranslmed.aax3519.
    1. Shen X.N., Niu L.D., Wang Y.J., Cao X.P., Liu Q., Tan L., Zhang C., Yu J.T. Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: A meta-analysis and systematic review of 170 studies. J. Neurol. Neurosurg. Psychiatry. 2019;90:590–598. doi: 10.1136/jnnp-2018-319148.
    1. Antonell A., Mansilla A., Rami L., Lladó A., Iranzo A., Olives J., Balasa M., Sánchez-Valle R., Molinuevo J.L. Cerebrospinal fluid level of YKL-40 protein in preclinical and prodromal Alzheimer’s disease. J. Alzheimers Dis. 2014;42:901–908. doi: 10.3233/JAD-140624.
    1. Kester M.I., Teunissen C.E., Sutphen C., Herries E.M., Ladenson J.H., Xiong C., Scheltens P., van der Flier W.M., Morris J.C., Holtzman D.M., et al. Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer’s disease in a memory clinic cohort. Alzheimers Res. Ther. 2015;7:59. doi: 10.1186/s13195-015-0142-1.
    1. Choi J., Lee H.W., Suk K. Plasma level of chitinase 3-like 1 protein increases in patients with early Alzheimer’s disease. J. Neurol. 2011;258:2181–2185. doi: 10.1007/s00415-011-6087-9.
    1. Daws M.R., Lanier L.L., Seaman W.E., Ryan J.C. Cloning and characterization of a novel mouse myeloid DAP12-associated receptor family. Eur. J. Immunol. 2001;31:783–791. doi: 10.1002/1521-4141(200103)31:3<783::AID-IMMU783>;2-U.
    1. Schmid C.D., Sautkulis L.N., Danielson P.E., Cooper J., Hasel K.W., Hilbush B.S., Sutcliffe J.G., Carson M.J. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J. Neurochem. 2002;83:1309–1320. doi: 10.1046/j.1471-4159.2002.01243.x.
    1. Takahashi K., Rochford C.D., Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 2005;201:647–657. doi: 10.1084/jem.20041611.
    1. Hu N., Tan M.S., Yu J.T., Sun L., Tan L., Wang Y.L., Jiang T. Increased expression of TREM2 in peripheral blood of Alzheimer’s disease patients. J. Alzheimers Dis. 2014;38:497–501. doi: 10.3233/JAD-130854.
    1. Casati M., Ferri E., Gussago C., Mazzola P., Abbate C., Bellelli G., Mari D., Cesari M., Arosio B. Increased expression of TREM2 in peripheral cells from mild cognitive impairment patients who progress into Alzheimer’s disease. Eur. J. Neurol. 2018;25:805–810. doi: 10.1111/ene.13583.
    1. Fahrenhold M., Rakic S., Classey J., Brayne C., Ince P.G., Nicoll J.A.R., Boche D., MRC-CFAS TREM2 expression in the human brain: A marker of monocyte recruitment? Brain Pathol. 2018;28:595–602. doi: 10.1111/bpa.12564.
    1. Jay T.R., Miller C.M., Cheng P.J., Graham L.C., Bemiller S., Broihier M.L., Xu G., Margevicius D., Karlo J.C., Sousa G.L., et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 2015;212:287–295. doi: 10.1084/jem.20142322.
    1. Frank S., Burbach G.J., Bonin M., Walter M., Streit W., Bechmann I., Deller T. TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia. 2008;56:1438–1447. doi: 10.1002/glia.20710.
    1. Lessard C.B., Malnik S.L., Zhou Y., Ladd T.B., Cruz P.E., Ran Y., Mahan T.E., Chakrabaty P., Holtzman D.M., Ulrich J.D., et al. High-affinity interactions and signal transduction between Aβ oligomers and TREM2. EMBO Mol. Med. 2018;10 doi: 10.15252/emmm.201809027.
    1. Ulrich J.D., Finn M.B., Wang Y., Shen A., Mahan T.E., Jiang H., Stewart F.R., Piccio L., Colonna M., Holtzman D.M. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 2014;9:20. doi: 10.1186/1750-1326-9-20.
    1. Zhao Y., Wu X., Li X., Jiang L.L., Gui X., Liu Y., Sun Y., Zhu B., Piña-Crespo J.C., Zhang M., et al. TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function. Neuron. 2018;97:1023.e7–1031.e7. doi: 10.1016/j.neuron.2018.01.031.
    1. Claes C., Van Den Daele J., Boon R., Schouteden S., Colombo A., Monasor L.S., Fiers M., Ordovás L., Nami F., Bohrmann B., et al. Human stem cell-derived monocytes and microglia-like cells reveal impaired amyloid plaque clearance upon heterozygous or homozygous loss of TREM2. Alzheimers Dement. 2019;15:453–464. doi: 10.1016/j.jalz.2018.09.006.
    1. Wunderlich P., Glebov K., Kemmerling N., Tien N.T., Neumann H., Walter J. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and γ-secretase-dependent intramembranous cleavage. J. Biol. Chem. 2013;288:33027–33036. doi: 10.1074/jbc.M113.517540.
    1. Heslegrave A., Heywood W., Paterson R., Magdalinou N., Svensson J., Johansson P., Öhrfelt A., Blennow K., Hardy J., Schott J., et al. Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease. Mol. Neurodegener. 2016;11:3. doi: 10.1186/s13024-016-0071-x.
    1. Bekris L.M., Khrestian M., Dyne E., Shao Y., Pillai J.A., Rao S.M., Bemiller S.M., Lamb B., Fernandez H.H., Leverenz J.B. Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease. J. Neuroimmunol. 2018;319:19–27. doi: 10.1016/j.jneuroim.2018.03.003.
    1. Suárez-Calvet M., Kleinberger G., Araque Caballero M., Brendel M., Rominger A., Alcolea D., Fortea J., Lleó A., Blesa R., Gispert J.D., et al. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer’s disease and associate with neuronal injury markers. EMBO Mol. Med. 2016;8:466–476. doi: 10.15252/emmm.201506123.
    1. Liu D., Cao B., Zhao Y., Huang H., McIntyre R.S., Rosenblat J.D., Zhou H. Soluble TREM2 changes during the clinical course of Alzheimer’s disease: A meta-analysis. Neurosci. Lett. 2018;686:10–16. doi: 10.1016/j.neulet.2018.08.038.
    1. Piccio L., Deming Y., Del-Águila J.L., Ghezzi L., Holtzman D.M., Fagan A.M., Fenoglio C., Galimberti D., Borroni B., Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016;131:925–933. doi: 10.1007/s00401-016-1533-5.
    1. Gispert J.D., Suárez-Calvet M., Monté G.C., Tucholka A., Falcon C., Rojas S., Rami L., Sánchez-Valle R., Lladó A., Kleinberger G., et al. Cerebrospinal fluid sTREM2 levels are associated with gray matter volume increases and reduced diffusivity in early Alzheimer’s disease. Alzheimers Dement. 2016;12:1259–1272. doi: 10.1016/j.jalz.2016.06.005.
    1. Zhong L., Xu Y., Zhuo R., Wang T., Wang K., Huang R., Wang D., Gao Y., Zhu Y., Sheng X., et al. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model. Nat. Commun. 2019;10:1365. doi: 10.1038/s41467-019-09118-9.
    1. Braestrup C., Albrechtsen R., Squires R.F. High densities of benzodiazepine receptors in human cortical areas. Nature. 1977;269:702–704. doi: 10.1038/269702a0.
    1. Park C.H., Carboni E., Wood P.L., Gee K.W. Characterization of peripheral benzodiazepine type sites in a cultured murine BV-2 microglial cell line. Glia. 1996;16:65–70. doi: 10.1002/(SICI)1098-1136(199601)16:1<65::AID-GLIA7>;2-A.
    1. Kuhlmann A.C., Guilarte T.R. Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity. J. Neurochem. 2000;74:1694–1704. doi: 10.1046/j.1471-4159.2000.0741694.x.
    1. Cosenza-Nashat M., Zhao M.L., Suh H.S., Morgan J., Natividad R., Morgello S., Lee S.C. Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol. Appl. Neurobiol. 2009;35:306–328. doi: 10.1111/j.1365-2990.2008.01006.x.
    1. Chen M.K., Guilarte T.R. Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair. Pharmacol. Ther. 2008;118:1–17. doi: 10.1016/j.pharmthera.2007.12.004.
    1. Bradburn S., Murgatroyd C., Ray N. Neuroinflammation in mild cognitive impairment and Alzheimer’s disease: A meta-analysis. Ageing Res. Rev. 2019;50:1–8. doi: 10.1016/j.arr.2019.01.002.
    1. Cagnin A., Brooks D.J., Kennedy A.M., Gunn R.N., Myers R., Turkheimer F.E., Jones T., Banati R.B. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358:461–467. doi: 10.1016/S0140-6736(01)05625-2.
    1. Kreisl W.C., Lyoo C.H., McGwier M., Snow J., Jenko K.J., Kimura N., Corona W., Morse C.L., Zoghbi S.S., Pike V.W., et al. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain. 2013;136:2228–2238. doi: 10.1093/brain/awt145.
    1. Tournier B.B., Tsartsalis S., Ceyzériat K., Fraser B.H., Grégoire M.C., Kövari E., Millet P. Astrocytic TSPO Upregulation Appears Before Microglial TSPO in Alzheimer’s Disease. J. Alzheimers Dis. 2020;77:1043–1056. doi: 10.3233/JAD-200136.
    1. Ferrarese C., Appollonio I., Frigo M., Meregalli S., Piolti R., Tamma F., Frattola L. Cerebrospinal fluid levels of diazepam-binding inhibitor in neurodegenerative disorders with dementia. Neurology. 1990;40:632–635. doi: 10.1212/WNL.40.4.632.
    1. Conti E., Andreoni S., Tomaselli D., Storti B., Brovelli F., Acampora R., Da Re F., Appollonio I., Ferrarese C., Tremolizzo L. Serum DBI and biomarkers of neuroinflammation in Alzheimer’s disease and delirium. Neurol. Sci. 2021;42:1003–1007. doi: 10.1007/s10072-020-04608-x.
    1. Clark C., Lewczuk P., Kornhuber J., Richiardi J., Maréchal B., Karikari T.K., Blennow K., Zetterberg H., Popp J. Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer’s disease pathology and clinical disease progression. Alzheimers Res. Ther. 2021;13:65. doi: 10.1186/s13195-021-00805-8.
    1. Torres-Acosta N., O’Keefe J.H., O’Keefe E.L., Isaacson R., Small G. Therapeutic Potential of TNF-α Inhibition for Alzheimer’s Disease Prevention. J. Alzheimers Dis. 2020;78:619–626. doi: 10.3233/JAD-200711.
    1. Lunardelli M.L., Crupi R., Siracusa R., Cocuzza G., Cordaro M., Martini E., Impellizzeri D., Di Paola R., Cuzzocrea S. Co-ultraPEALut: Role in Preclinical and Clinical Delirium Manifestations. CNS Neurol. Disord. Drug Targets. 2019;18:530–554. doi: 10.2174/1871527318666190617162041.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren