Rola TREM2 w leczeniu choroby Alzheimera
Słowa kluczowe:
Choroba Alzheimera, Demencja, TREM2, Terapia celowanaStreszczenie
Choroba Alzheimera (AD) jest chorobą neurodegeneracyjną, cechującą się postępującym w czasie pogorszeniem funkcji poznawczych pacjenta. Histopatologicznie AD spowodowane jest nagromadzeniem się złogów białka Tau i amyloidu-β w tkance nerwowej. Obecnie nie ma skutecznego leczenia na AD, dlatego też choroba ta stanowi coraz poważniejszy problem kliniczny. Duże nadzieje w kontekście leczenia AD pokłada się jednak w receptorach TREM2, które ulegają ekspresji między innymi na makrofagach i komórkach mikrogleju. Uważa się, że TREM2 promują przeżywalność komórek oraz zdolności fagocytarne, co więcej donosi się również, że mogą one brać udział w hamowaniu procesów zapalnych. Badania na zwierzętach wykazały, że TREM2 bierze udział w otaczaniu złogów amyloidu-β, tym samym przyczyniając się do redukcji postępu choroby. Ponadto, badania genetyczne wykazały, że istnieją warianty TREM2 sprzężone z AD. Z tego względu receptory TREM2 mogą w przyszłości stanowić wartościowy cel terapeutyczny dla terapii AD.
Bibliografia
Crous-Bou M, Minguillón C, Gramunt N, et al.: Alzheimer's disease prevention: from risk factors to early intervention. Alzheimers Res Ther. 2017;9(1):71. 10.1186/s13195-017-0297-z
C. P World Alzheimer report 2018. London: Alzheimer’s Disease International, 2018.
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2011;1(1):a006189. doi:10.1101/cshperspect.a006189
Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron. 2010;68(2):270-281. doi:10.1016/j.neuron.2010.10.013
Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer's disease: accidental encounters or partners?. Neuron. 2014;81(4):740-754. doi:10.1016/j.neuron.2014.01.045
Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921-923. doi:10.1126/science.8346443
Bhattacharjee S, Zhao Y, Dua P, Rogaev EI, Lukiw WJ. microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration [published correction appears in PLoS One. 2016;11(4):e0153292]. PLoS One. 2016;11(3):e0150211. Published 2016 Mar 7. doi:10.1371/journal.pone.0150211
Bouchon A, Hernández-Munain C, Cella M, Colonna M. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med. 2001;194(8):1111-1122. doi:10.1084/jem.194.8.1111
Schmid CD, Sautkulis LN, Danielson PE, et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem. 2002;83(6):1309-1320. doi:10.1046/j.1471-4159.2002.01243.x
Chertoff M, Shrivastava K, Gonzalez B, Acarin L, Giménez-Llort L. Differential modulation of TREM2 protein during postnatal brain development in mice. PLoS One. 2013;8(8):e72083. Published 2013 Aug 19. doi:10.1371/journal.pone.0072083
Forabosco P, Ramasamy A, Trabzuni D, et al. Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol Aging. 2013;34(12):2699-2714. doi:10.1016/j.neurobiolaging.2013.05.001
Lue LF, Schmitz CT, Serrano G, Sue LI, Beach TG, Walker DG. TREM2 Protein Expression Changes Correlate with Alzheimer's Disease Neurodegenerative Pathologies in Post-Mortem Temporal Cortices. Brain Pathol. 2015;25(4):469-480. doi:10.1111/bpa.12190
Perez SE, Nadeem M, He B, et al. Neocortical and hippocampal TREM2 protein levels during the progression of Alzheimer's disease. Neurobiol Aging. 2017;54:133-143. doi:10.1016/j.neurobiolaging.2017.02.012
Celarain N, Sánchez-Ruiz de Gordoa J, Zelaya MV, et al. TREM2 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer's disease hippocampus. Clin Epigenetics. 2016;8:37. Published 2016 Apr 5. doi:10.1186/s13148-016-0202-9
Jiang T, Tan L, Zhu XC, et al. Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease. Neuropsychopharmacology. 2014;39(13):2949-2962. doi:10.1038/npp.2014.164
Peng Q, Malhotra S, Torchia JA, Kerr WG, Coggeshall KM, Humphrey MB. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal. 2010;3(122):ra38. Published 2010 May 18. doi:10.1126/scisignal.2000500
Kleinberger G, Brendel M, Mracsko E, et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017;36(13):1837-1853. doi:10.15252/embj.201796516
Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med. 2005;201(4):647-657. doi:10.1084/jem.20041611
Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M. TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 2016;91(2):328-340. doi:10.1016/j.neuron.2016.06.015
N'Diaye EN, Branda CS, Branda SS, et al. TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J Cell Biol. 2009;184(2):215-223. doi:10.1083/jcb.200808080
Jaitin DA, Adlung L, Thaiss CA, et al. Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell. 2019;178(3):686-698.e14. doi:10.1016/j.cell.2019.05.054
Keren-Shaul H, Spinrad A, Weiner A, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017;169(7):1276-1290.e17. doi:10.1016/j.cell.2017.05.018
Kober DL, Brett TJ. TREM2-Ligand Interactions in Health and Disease. J Mol Biol. 2017;429(11):1607-1629. doi:10.1016/j.jmb.2017.04.004
Ulland TK, Song WM, Huang SC, et al. TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell. 2017;170(4):649-663.e13. doi:10.1016/j.cell.2017.07.023
Wang Y, Cella M, Mallinson K, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015;160(6):1061-1071. doi:10.1016/j.cell.2015.01.049
Otero K, Shinohara M, Zhao H, et al. TREM2 and β-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis [published correction appears in J Immunol. 2012 Jun 1;188(11):5802]. J Immunol. 2012;188(6):2612-2621. doi:10.4049/jimmunol.1102836
Paloneva J, Manninen T, Christman G, et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype [published correction appears in Am J Hum Genet. 2003 Jan;72(1):225.]. Am J Hum Genet. 2002;71(3):656-662. doi:10.1086/342259
Guerreiro RJ, Lohmann E, Brás JM, et al. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013;70(1):78-84. doi:10.1001/jamaneurol.2013.579
Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013;368(2):117-127. doi:10.1056/NEJMoa1211851
Slattery CF, Beck JA, Harper L, et al. R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia. Alzheimers Dement. 2014;10(6):602-608.e4. doi:10.1016/j.jalz.2014.05.1751
Cuyvers E, Sleegers K. Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond. Lancet Neurol. 2016;15(8):857-868. doi:10.1016/S1474-4422(16)00127-7
Benitez BA, Cooper B, Pastor P, et al. TREM2 is associated with the risk of Alzheimer's disease in Spanish population. Neurobiol Aging. 2013;34(6):1711.e15-1711.e17. doi:10.1016/j.neurobiolaging.2012.12.018
Finelli D, Rollinson S, Harris J, et al. TREM2 analysis and increased risk of Alzheimer's disease. Neurobiol Aging. 2015;36(1):546.e9-546.e5.46E13. doi:10.1016/j.neurobiolaging.2014.08.001
Ghani M, Sato C, Kakhki EG, et al. Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set. Neurobiol Aging. 2016;42:217.e7-217.e13. doi:10.1016/j.neurobiolaging.2016.03.009
Yu JT, Jiang T, Wang YL, et al. Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer's disease in Han Chinese individuals. Neurobiol Aging. 2014;35(4):937.e1-937.e9373. doi:10.1016/j.neurobiolaging.2013.10.075
Ma J, Zhou Y, Xu J, et al. Association study of TREM2 polymorphism rs75932628 with late-onset Alzheimer's disease in Chinese Han population. Neurol Res. 2014;36(10):894-896. doi:10.1179/1743132814Y.0000000376
Jin SC, Benitez BA, Karch CM, et al. Coding variants in TREM2 increase risk for Alzheimer's disease. Hum Mol Genet. 2014;23(21):5838-5846. doi:10.1093/hmg/ddu277
Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci. 2016;17(4):201-207. doi:10.1038/nrn.2016.7
Yuan P, Condello C, Keene CD, et al. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron. 2016;90(4):724-739. doi:10.1016/j.neuron.2016.05.003
Wang Y, Ulland TK, Ulrich JD, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016;213(5):667-675. doi:10.1084/jem.20151948
Jay TR, Hirsch AM, Broihier ML, et al. Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease. J Neurosci. 2017;37(3):637-647. doi:10.1523/JNEUROSCI.2110-16.2016
Jay TR, Miller CM, Cheng PJ, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med. 2015;212(3):287-295. doi:10.1084/jem.20142322
Lee CYD, Daggett A, Gu X, et al. Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models. Neuron. 2018;97(5):1032-1048.e5. doi:10.1016/j.neuron.2018.02.002
Kleinberger G, Yamanishi Y, Suárez-Calvet M, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014;6(243):243ra86. doi:10.1126/scitranslmed.3009093
Ma L, Allen M, Sakae N, et al. Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer's disease brains. Mol Neurodegener. 2016;11(1):72. Published 2016 Nov 25. doi:10.1186/s13024-016-0137-9
Yin J, Liu X, He Q, Zhou L, Yuan Z, Zhao S. Vps35-dependent recycling of Trem2 regulates microglial function. Traffic. 2016;17(12):1286-1296. doi:10.1111/tra.12451
Bailey CC, DeVaux LB, Farzan M. The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E. J Biol Chem. 2015;290(43):26033-26042. doi:10.1074/jbc.M115.677286
Atagi Y, Liu CC, Painter MM, et al. Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). J Biol Chem. 2015;290(43):26043-26050. doi:10.1074/jbc.M115.679043
Zajkowicz A, Gdowicz-Kłosok A, Krześniak M, Janus P, Łasut B, Rusin M. The Alzheimer's disease-associated TREM2 gene is regulated by p53 tumor suppressor protein. Neurosci Lett. 2018;681:62-67. doi:10.1016/j.neulet.2018.05.037
Ulland TK, Song WM, Huang SC, et al. TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell. 2017;170(4):649-663.e13. doi:10.1016/j.cell.2017.07.023
Mazaheri F, Snaidero N, Kleinberger G, et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 2017;18(7):1186-1198. doi:10.15252/embr.201743922
Keren-Shaul H, Spinrad A, Weiner A, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017;169(7):1276-1290.e17. doi:10.1016/j.cell.2017.05.018
Krasemann S, Madore C, Cialic R, et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017;47(3):566-581.e9. doi:10.1016/j.immuni.2017.08.008
Leyns CEG, Ulrich JD, Finn MB, et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017;114(43):11524-11529. doi:10.1073/pnas.1710311114
Jiang T, Tan L, Zhu XC, et al. Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice. Neurobiol Aging. 2015;36(12):3176-3186. doi:10.1016/j.neurobiolaging.2015.08.019
Bemiller SM, McCray TJ, Allan K, et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener. 2017;12(1):74. Published 2017 Oct 16. doi:10.1186/s13024-017-0216-6
Strike SC, Carlisle A, Gibson EL, Dyall SC. A High Omega-3 Fatty Acid Multinutrient Supplement Benefits Cognition and Mobility in Older Women: A Randomized, Double-blind, Placebo-controlled Pilot Study. J Gerontol A Biol Sci Med Sci. 2016;71(2):236-242. doi:10.1093/gerona/glv109
Lee LK, Shahar S, Chin AV, Yusoff NA. Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacology (Berl). 2013;225(3):605-612. doi:10.1007/s00213-012-2848-0
Qin Z, Gu M, Zhou J, et al. Triggering receptor expressed on myeloid cells 2 activation downregulates toll-like receptor 4 expression and ameliorates cognitive impairment in the Aβ1-42 -induced Alzheimer's disease mouse model. Synapse. 2020;74(10):e22161. doi:10.1002/syn.22161
Wang Y, Cella M, Mallinson K, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015;160(6):1061-1071. doi:10.1016/j.cell.2015.01.049
Bouchon A, Hernández-Munain C, Cella M, Colonna M. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med. 2001;194(8):1111-1122. doi:10.1084/jem.194.8.1111
Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 2007;4(4):e124. doi:10.1371/journal.pmed.0040124
Price BR, Sudduth TL, Weekman EM, et al. Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition. J Neuroinflammation. 2020;17(1):238. Published 2020 Aug 14. doi:10.1186/s12974-020-01915-0
Fitz NF, Nam KN, Wolfe CM, et al. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer's disease. Nat Commun. 2021;12(1):3416. Published 2021 Jun 7. doi:10.1038/s41467-021-23762-0
Ruganzu JB, Zheng Q, Wu X, et al. TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway. Exp Neurol. 2021;336:113506. doi:10.1016/j.expneurol.2020.113506
Sheng L, Chen M, Cai K, et al. Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP/PS1 mice. FASEB J. 2019;33(9):10425-10442. doi:10.1096/fj.201900527R
Cramer PE, Cirrito JR, Wesson DW, et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science. 2012;335(6075):1503-1506. doi:10.1126/science.1217697
Savage JC, Jay T, Goduni E, et al. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer's disease. J Neurosci. 2015;35(16):6532-6543. doi:10.1523/JNEUROSCI.4586-14.2015
Griciuc A, Patel S, Federico AN, et al. TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease. Neuron. 2019;103(5):820-835.e7. doi:10.1016/j.neuron.2019.06.010
Lefterov I, Schug J, Mounier A, Nam KN, Fitz NF, Koldamova R. RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment. Neurobiol Dis. 2015;82:132-140. doi:10.1016/j.nbd.2015.05.019
Konishi H, Kiyama H. Microglial TREM2/DAP12 Signaling: A Double-Edged Sword in Neural Diseases. Front Cell Neurosci. 2018;12:206. Published 2018 Aug 6. doi:10.3389/fncel.2018.00206
Tesseur I, Lo AC, Roberfroid A, et al. Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013;340(6135):. doi:10.1126/science.1233937
Tachibana M, Shinohara M, Yamazaki Y, et al. Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp Neurol. 2016;277:1-9. doi:10.1016/j.expneurol.2015.12.003
Park M, Yi JW, Kim EM, et al. Triggering receptor expressed on myeloid cells 2 (TREM2) promotes adipogenesis and diet-induced obesity. Diabetes. 2015;64(1):117-127. doi:10.2337/db13-1869
Fujimoto S, Goda T, Mochizuki K. In vivo evidence of enhanced di-methylation of histone H3 K4 on upregulated genes in adipose tissue of diabetic db/db mice. Biochem Biophys Res Commun. 2011;404(1):223-227. doi:10.1016/j.bbrc.2010.11.097
Liu C, Li P, Li H, et al. TREM2 regulates obesity-induced insulin resistance via adipose tissue remodeling in mice of high-fat feeding. J Transl Med. 2019;17(1):300. Published 2019 Sep 2. doi:10.1186/s12967-019-2050-9
Hou J, Zhang J, Cui P, et al. TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis. J Clin Invest. 2021;131(4):e135197. doi:10.1172/JCI135197
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13 lipca 2024
Prawa autorskie (c) 2024 Maciej Baron, Bartosz Bula, Natalia Ubysz, Łukasz Zniszczoł, Andrzej Skrzypiec, Anna Budzyńska, Małgorzata Wachowicz
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Utwór dostępny jest na licencji Creative Commons Uznanie autorstwa – Użycie niekomercyjne – Bez utworów zależnych 4.0 Międzynarodowe.
