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Cited by 16Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammation biomarkers and pathways

TREM2 in neurodegeneration and diseases

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Abdulkhaliq, Altaf A., Alasiri, Glowi, Kim, Bonglee, Khan, Johra, Ajoolabady, Amir, Yousof, Shimaa Mohammad, Ren, Jun, Tuomilehto, Jaakko +3 more·2026·Molecular Psychiatry
DOI 10.1038/s41380-026-03505-7PMC PMC13268972
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Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface transmembrane receptor from the TREM receptor family, predominantly expressed on the microglia in the central nervous system (CNS). TREM2-initiated signaling plays a crucial role in regulating neuroinflammation and neurodegeneration, particularly in the context of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), through the activation of downstream signaling pathways and transcriptional regulation of relevant genes. In this review, we aim to provide a concise review of the role and mechanistic implications of TREM2 in neurodegeneration and neuroinflammation, with a specific focus on AD and PD. We will discuss the most recent preclinical studies to highlight current advancements in the field. This review is intended to support both basic researchers and clinicians by enhancing their understanding of microglial function in the pathophysiology of AD and PD, as well as its role in neuroinflammation and neurodegeneration. Ultimately, we hope this contribution will pave the way for new discoveries and the development of potential therapeutic interventions.

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  • Pathways that support amyloid plaque response may have different consequences in tau-rich or late-stage disease.

    “pathways that support amyloid plaque response may have different consequences in tau-rich or late-stage disease [55,60]”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [60]

    The section on TREM2 in Alzheimer’s-associated neuroinflammation says TREM2 can support amyloid-β responses yet may have different effects when tau pathology occurs, supporting the tau-related part of the claim. It does not establish the same distinction specifically for late-stage disease; its stage-specific discussion concerns early- and middle-stage models. No page numbers are available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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  1. [2]Levi S, Ripamonti M, Moro AS, Cozzi A. Iron imbalance in neurodegeneration. Mol Psychiatry. 2024;29:1139–52. 38212377 PMC11176077 · DOI
  2. [3]Goedert M, Crowther RA, Scheres SH, Spillantini MG. Tau and neurodegeneration. Cytoskeleton. 2024;81:95–102. 38073060 PMC7615684 · DOI
  3. [4]Ruitenberg MF. Cognition and movement in neurodegenerative disorders: a dynamic duo. Neural Regen Res. 2024;19:2101–2. 38488538 PMC11034590 · DOI
  4. [5]Chi H, Chang H-Y, Sang T-K. Neuronal cell death mechanisms in major neurodegenerative diseases. Int J Mol Sci. 2018;19:3082. 30304824 PMC6213751 · DOI · Paper page
  5. [6]Jellinger KA. Basic mechanisms of neurodegeneration: a critical update. J Cell Mol Med. 2010;14:457–87. 20070435 PMC3823450 · DOI
  6. [7]Jellinger KA. Recent advances in our understanding of neurodegeneration. J Neural Transm. 2009;116:1111–62. 19707851 · DOI · Paper page
  7. [8]Skovronsky DM, Lee VM-Y, Trojanowski JQ. Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol Mech Dis. 2006;1:151–70. 18039111 · DOI
  8. [9]Brunelli S, Giannella E, Bizzaglia M, De Angelis D, Sancesario GM. Secondary neurodegeneration following Stroke: what can blood biomarkers tell us? Front Neurol. 2023;14:1198216. 37719764 PMC10502514 · DOI
  9. [10]Crews FT, Nixon K. Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcohol. 2009;44:115–27. 18940959 PMC2948812 · DOI
  10. [11]Savaskan NE, Fan Z, Broggini T, Buchfelder M, Eyupoglu IY. Neurodegeneration in the brain tumor microenvironment: Glutamate in the limelight. Curr Neuropharmacol. 2015;13:258–65. 26411769 PMC4598438 · DOI
  11. [12]Danysz W. Neurotoxicity as a mechanism for neurodegenerative disorders: basic and clinical aspects. Expert Opin Investig Drugs. 2001;10:985–9. 11424902 · DOI
  12. [13]Limongi D, Baldelli S. Redox imbalance and viral infections in neurodegenerative diseases. Oxid Med Cell Longev. 2016;2016:6547248. 27110325 PMC4826696 · DOI
  13. [16]Angeloni C, Malaguti M, Prata C, Freschi M, Barbalace MC, Hrelia S. Mechanisms underlying neurodegenerative disorders and potential neuroprotective activity of agrifood by-products. Antioxidants. 2022;12:94. 36670956 PMC9854890 · DOI
  14. [17]Xie A, Gao J, Xu L, Meng D. Shared mechanisms of neurodegeneration in Alzheimer’s disease and Parkinson’s disease. Biomed Res Int. 2014;2014:648740. 24900975 PMC4037122 · DOI
  15. [18]Perl DP, Warren CO, Calne D. Alzheimer’s disease and Parkinson’s disease: distinct entities or extremes of a spectrum of neurodegeneration? Ann Neurol. 1998;44:S19–S31. 9749570 · DOI
  16. [19]Khan J, Rudrapal M, Bhat EA, Ali A, Alaidarous M, Alshehri B, et al. Perspective insights to bio-nanomaterials for the treatment of neurological disorders. Front Bioeng Biotechnol. 2021;9:724158. 34712651 PMC8546296 · DOI
  17. [20]Rajmohan R, Reddy PH. Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer’s disease neurons. J Alzheimer’s Dis. 2017;57:975–99. 27567878 PMC5793225 · DOI
  18. [21]Chen X-Q, Mobley WC. Alzheimer disease pathogenesis: insights from molecular and cellular biology studies of oligomeric Aβ and tau species. Front Neurosci. 2019;13:659. 31293377 PMC6598402 · DOI
  19. [23]Bishop GM, Robinson SR. Physiological roles of amyloid-β and implications for its removal in Alzheimer’s disease. Drugs Aging. 2004;21:621–30. 15287821 · DOI · Paper page
  20. [24]Chen G-f, Xu T-h, Yan Y, Zhou Y-r, Jiang Y, Melcher K, et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin. 2017;38:1205–35. 28713158 PMC5589967 · DOI · Paper page
  21. [25]Kumar DKV, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med. 2016;8:340ra372–340ra372. PMC5505565 27225182 · DOI · Paper page
  22. [28]Wang S, Mims PN, Roman RJ, Fan F. Is beta-amyloid accumulation a cause or consequence of Alzheimer’s disease? J Alzheimer’s Parkinsonism Dementia. 2016;1:007. PMC5555607 28815226
  23. [29]Pluta R, Ułamek M, Jabłoński M. Alzheimer’s mechanisms in ischemic brain degeneration. Anat Rec: Advances in Integrative Anatomy and Evolutionary Biology: Advances in Integrative Anatomy and Evolutionary Biology. 2009;292:1863–81. 19943340 · DOI
  24. [30]Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci. 1998;95:6469–73. 9600990 PMC27806 · DOI
  25. [32]Lang AE, Siderowf AD, Macklin EA, Poewe W, Brooks DJ, Fernandez HH, et al. Trial of cinpanemab in early Parkinson’s disease. N Engl J Med. 2022;387:408–20. 35921450 · DOI
  26. [33]Vázquez-Vélez GE, Zoghbi HY. Parkinson’s disease genetics and pathophysiology. Annu Rev Neurosci. 2021;44:87–108. 34236893 · DOI
  27. [34]Weintraub D, Aarsland D, Chaudhuri KR, Dobkin RD, Leentjens AF, Rodriguez-Violante M, et al. The neuropsychiatry of Parkinson’s disease: advances and challenges. Lancet Neurol. 2022;21:89–102. 34942142 PMC8800169 · DOI
  28. [35]Protter D, Lang C, Cooper AA. αSynuclein and mitochondrial dysfunction: A pathogenic partnership in Parkinson’s disease? Parkinson’s Dis. 2012;2012:829207. 22737587 PMC3377350
  29. [36]Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson’s disease. Parkinsonism Relat Disord. 2007;13:323–32. 17349813 · DOI
  30. [37]Han MN, Finkelstein DI, McQuade RM, Diwakarla S. Gastrointestinal dysfunction in Parkinson’s disease: current and potential therapeutics. J Pers Med. 2022;12:144. 35207632 PMC8875119 · DOI
  31. [38]Zhao N, Zhang Q, Yu F, Yao X, Liu H. The α-Synuclein monomer may have different misfolding mechanisms in the induction of α-Synuclein Fibrils with different polymorphs. Biomolecules. 2023;13:682. 37189428 PMC10136287 · DOI
  32. [39]Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;14:38–48. 23254192 PMC4295774 · DOI
  33. [40]Manzanza NdO, Sedlackova L, Kalaria RN. Alpha-synuclein post-translational modifications: implications for pathogenesis of lewy body disorders. Front Aging Neurosci. 2021;13:690293. 34248606 PMC8267936 · DOI
  34. [41]Nikoletopoulou V, Tavernarakis N. The PMR1 pump in alpha-synuclein toxicity and neurodegeneration. Neurosci Lett. 2018;663:66–71. 28780169 · DOI
  35. [42]Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho WH, Castillo PE, et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25:239–52. 10707987 · DOI · Paper page
  36. [43]Asl MM, Vahabie A-H, Valizadeh A. Dopaminergic modulation of synaptic plasticity, its role in neuropsychiatric disorders, and its computational modeling. Basic Clin Neurosci. 2019;10:1. 31031889 PMC6484184
  37. [44]Recasens A, Dehay B, Bové J, Carballo‐Carbajal I, Dovero S, Pérez‐Villalba A, et al. Lewy body extracts from Parkinson disease brains trigger α‐synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol. 2014;75:351–62. 24243558 · DOI
  38. [45]Negi S, Khurana N, Duggal N. The misfolding mystery: α-syn and the pathogenesis of Parkinson’s disease. Neurochem Int. 2024;177:105760. 38723900 · DOI
  39. [46]Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4:160–4. 11813001 · DOI
  40. [47]Hasegawa M, Fujiwara H, Nonaka T, Wakabayashi K, Takahashi H, Lee VM-Y, et al. Phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions. J Biol Chem. 2002;277:49071–6. 12377775 · DOI · Paper page
  41. [48]Price DL, Khan A, Angers R, Cardenas A, Prato MK, Bani M, et al. In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease. npj Parkinson’s Dis. 2023;9:114. 37460603 PMC10352257 · DOI
  42. [49]Calabresi P, Mechelli A, Natale G, Volpicelli-Daley L, Di Lazzaro G, Ghiglieri V. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: From overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 2023;14:176. 36859484 PMC9977911 · DOI
  43. [51]Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G. Neuroinflammation pathways: A general review. Int J Neurosci. 2017;127:624–33. 27412492 · DOI
  44. [52]Becher B, Spath S, Goverman J. Cytokine networks in neuroinflammation. Nat Rev Immunol. 2017;17:49–59. 27916979 · DOI
  45. [53]Rudrapal M, de Oliveira AM, de Abreu HA, Rakshit G, Tripathi MK, Khan J. Anti‐Inflammatory and Antioxidant Potential of Plant‐Derived Phenolic Acids as Triple COX, LOX, and NOX Inhibitors: A Computational Approach. Chem Biodivers. 2025;22:e03505. 40479651 · DOI
  46. [54]Kumar D, Jahan S, Khan A, Siddiqui AJ, Redhu NS, Wahajuddin, et al. Neurological manifestation of SARS-CoV-2 induced inflammation and possible therapeutic strategies against COVID-19. Mol Neurobiol. 2021;58:3417–34. 33715108 PMC7955900 · DOI
  47. [55]Iwu RC, Amie DC, Eduwa OA, Sanusi-Borokini MA, Augustine FA, Zakari AO. Prevalence of pelvic inflammatory disease among women of reproductive age attending Gynaecology Clinic at Lagos State University Teaching Hospital, Ikeja, Lagos. Scicom J Med Appl Med Sci. 2024;3:45–50. · DOI
  48. [56]Ransohoff RM, Schafer D, Vincent A, Blachère NE, Bar-Or A. Neuroinflammation: ways in which the immune system affects the brain. Neurotherapeutics. 2015;12:896–909. 26306439 PMC4604183 · DOI
  49. [57]Ní Chasaide C, Lynch MA. The role of the immune system in driving neuroinflammation. Brain Neurosci Adv. 2020;4:2398212819901082. 32219178 PMC7085916 · DOI · Paper page
  50. [58]Peferoen L, Kipp M, van der Valk P, van Noort JM, Amor S. Oligodendrocyte‐microglia cross‐talk in the central nervous system. Immunology. 2014;141:302–13. 23981039 PMC3930369 · DOI · Paper page
  51. [59]Kölliker-Frers R, Udovin L, Otero-Losada M, Kobiec T, Herrera MI, Palacios J, et al. Neuroinflammation: An integrating overview of reactive‐Neuroimmune cell interactions in health and disease. Mediators Inflamm. 2021;2021:9999146. 34158806 PMC8187052 · DOI · Paper page
  52. [60]Soulet D, Rivest S. Microglia. Curr Biol. 2008;18:R506–R508. 18579087 · DOI
  53. [61]Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35:441–68. 28226226 PMC8167938 · DOI · Paper page
  54. [62]Kwon HS, Koh S-H. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020;9:42. 33239064 PMC7689983 · DOI · Paper page
  55. [64]Microglia-mediated neuroinflammation in neurodegenerative diseases. Proceedings of the Seminars in cell & developmental biology 2019. Elsevier. 31077796
  56. [65]Adetuyi BO, Toloyai P-EY, Ojugbeli ET, Oyebanjo OT, Adetuyi OA, Uche CZ, et al. Neurorestorative roles of microgliosis and astrogliosis in neuroinflammation and neurodegeneration. Scicom J Med Appl Med Sci. 2021;1:1–5. · DOI
  57. [66]Adamu A, Li S, Gao F, Xue G. The role of neuroinflammation in neurodegenerative diseases: Current understanding and future therapeutic targets. Front Aging Neurosci. 2024;16:1347987. 38681666 PMC11045904 · DOI · Paper page
  58. [67]Kempuraj D, Thangavel R, Natteru P, Selvakumar G, Saeed D, Zahoor H, et al. Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine. 2016;1:1003. 28127589 PMC5260818
  59. [69]Bhat EA, Sajjad N, Banawas S, Khan J. Human CALHM5: Insight in large pore lipid gating ATP channel and associated neurological pathologies. Mol Cell Biochem. 2021;476:3711–8. 34089472 · DOI
  60. [70]Di Filippo M, Chiasserini D, Tozzi A, Picconi B, Calabresi P. Mitochondria and the link between neuroinflammation and neurodegeneration. J Alzheimer’s Dis. 2010;20:S369–S379. 20463396 · DOI
  61. [71]Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases. Mol Med Rep. 2016;13:3391–6. 26935478 PMC4805095 · DOI
  62. [72]Miller RJ, Rostene W, Apartis E, Banisadr G, Biber K, Milligan ED, et al. Chemokine action in the nervous system. J Neurosci. 2008;28:11792–5. 19005041 PMC2746239 · DOI
  63. [73]Khan J, Tatli II. Stem cells vs exosomes: Promising therapeutic approach and biomarkers agent against neurodegenerative disorders. Applications of Stem Cells and derived Exosomes in Neurodegenerative Disorders. Springer; 2023. p. 169–91.
  64. [74]LaRocca TJ, Cavalier AN, Roberts CM, Lemieux MR, Ramesh P, Garcia MA, et al. Amyloid beta acts synergistically as a pro-inflammatory cytokine. Neurobiol Dis. 2021;159:105493. 34464705 PMC8502211 · DOI
  65. [76]Khodadadei F, Arshad R, Morales DM, Gluski J, Marupudi NI, McAllister JP, et al. The effect of A1 and A2 reactive astrocyte expression on hydrocephalus shunt failure. Fluids Barriers CNS. 2022;19:78. 36171630 PMC9516791 · DOI
  66. [82]Li Y, Xu H, Wang H, Yang K, Luan J, Wang S. TREM2: Potential therapeutic targeting of microglia for Alzheimer’s disease. Biomed Pharmacother. 2023;165:115218. 37517293 · DOI
  67. [83]Forabosco P, Ramasamy A, Trabzuni D, Walker R, Smith C, Bras J, et al. Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol Aging. 2013;34:2699–714. 23855984 PMC3988951 · DOI · Paper page
  68. [85]Liu G, Liu Y, Jiang Q, Jiang Y, Feng R, Zhang L, et al. Convergent genetic and expression datasets highlight TREM2 in Parkinson’s disease susceptibility. Mol Neurobiol. 2016;53:4931–8. 26365049 · DOI
  69. [86]Saber M, Kokiko-Cochran O, Puntambekar SS, Lathia JD, Lamb BT. Triggering receptor expressed on myeloid cells 2 deficiency alters acute macrophage distribution and improves recovery after traumatic brain injury. J Neurotrauma. 2017;34:423–35. 26976047 · DOI
  70. [87]Celarain N, Sánchez-Ruiz de Gordoa J, Zelaya MV, Roldán M, Larumbe R, Pulido L, et al. TREM2 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer’s disease hippocampus. Clin Epigenetics. 2016;8:1–10. 27051467 PMC4820985 · DOI
  71. [88]Ren M, Guo Y, Wei X, Yan S, Qin Y, Zhang X, et al. TREM2 overexpression attenuates neuroinflammation and protects dopaminergic neurons in experimental models of Parkinson’s disease. Exp Neurol. 2018;302:205–13. 29407460 · DOI
  72. [90]Xu J, Zhang L, Li M, He X, Luo J, Wu R, et al. TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair. J Neuroinflammation. 2023;20:50. 36829205 PMC9960657 · DOI
  73. [91]Jahan S, Redhu NS, Siddiqui AJ, Iqbal D, Khan J, Banawas S, et al. Nobiletin as a neuroprotectant against NMDA receptors: an in silico approach. Pharmaceutics. 2022;14:1123. 35745697 PMC9229780 · DOI
  74. [92]Li R, Wang X, He P. The most prevalent rare coding variants of TREM2 conferring risk of Alzheimer’s disease: A systematic review and meta‑analysis. Exp Ther Med. 2021;21:1–1. 33732320 PMC7903442 · DOI
  75. [93]Xue F, Du H. TREM2 mediates microglial anti-inflammatory activations in Alzheimer’s disease: lessons learned from transcriptomics. Cells. 2021;10:321. 33557250 PMC7913972 · DOI
  76. [94]Li C, Zhao B, Lin C, Gong Z, An X. TREM2 inhibits inflammatory responses in mouse microglia by suppressing the PI3K/NF‐κB signaling. Cell Biol Int. 2019;43:360–72. 29663649 PMC7379930 · DOI
  77. [95]Zhai Q, Li F, Chen X, Jia J, Sun S, Zhou D, et al. Triggering receptor expressed on myeloid cells 2, a novel regulator of immunocyte phenotypes, confers neuroprotection by relieving neuroinflammation. Anesthesiology. 2017;127:98–110. 28398927 · DOI
  78. [96]Ye P, Xu D, Xu J, Liu G, Huang S, Zhang W, et al. TREM-2 negatively regulates LPS-mediated inflammatory response in rat bone marrow-derived MSCs. Mol Med Rep. 2017;16:4777–83. 28849042 PMC5647029 · DOI
  79. [97]Lee B, Kim T-H, Jun J-B, Yoo D-H, Woo J-H, Choi SJ, et al. Direct inhibition of human RANK+ osteoclast precursors identifies a homeostatic function of IL-1β. J Immunol. 2010;185:5926–34. 20935210 PMC3016227 · DOI
  80. [98]Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L, et al. Cutting edge: TREM-2 attenuates macrophage activation. J Immunol. 2006;177:3520–4. 16951310 · DOI · Paper page
  81. [99]Zheng H, Liu C-C, Atagi Y, Chen X-F, Jia L, Yang L, et al. Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation. Neurobiol Aging. 2016;42:132–41. 27143430 PMC4857884 · DOI · Paper page
  82. [100]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. PLoS ONE. 2016;11:e0150211. 26949937 PMC4780721 · DOI · Paper page
  83. [102]Jiang T, Tan L, Zhu X-C, Zhang Q-Q, Cao L, Tan M-S, et al. Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2014;39:2949–62. 25047746 PMC4229581 · DOI · Paper page
  84. [103]Lane RM, Farlow MR. Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer’s disease. J Lipid Res. 2005;46:949–68. 15716586 · DOI
  85. [104]McMillan IO, Liang L, Su G, Song X, Drago K, Yang H, et al. TREM2 on microglia cell surface binds to and forms functional binary complexes with heparan sulfate modified with 6-O-sulfation and iduronic acid. J Biol Chem. 2024;300:107691. 39159814 PMC11416269 · DOI
  86. [105]Yen J-HJ, Yu I-CI. The role of ApoE-mediated microglial lipid metabolism in brain aging and disease. Immunometabolism. 2023;5:e00018. 36710921 PMC9869962 · DOI
  87. [106]Laskowitz DT, Matthew WD, Bennett ER, Schmechel D, Herbstreith MH, Goel S, et al. Endogenous apolipoprotein E suppresses LPS-stimulated microglial nitric oxide production. Neuroreport. 1998;9:615–8. 9559926 · DOI
  88. [107]Lynch JR, Tang W, Wang H, Vitek MP, Bennett ER, Sullivan PM, et al. APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem. 2003;278:48529–33. 14507923 · DOI · Paper page
  89. [108]Vitek MP, Brown CM, Colton CA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging. 2009;30:1350–60. 18155324 PMC2782461 · DOI · Paper page
  90. [109]Mai Z, Wei W, Yu H, Chen Y, Wang Y, Ding Y. Molecular recognition of the interaction between ApoE and the TREM2 protein. Transl Neurosci. 2022;13:93–103. 35582645 PMC9055258 · DOI
  91. [110]Huang Y-WA, Zhou B, Nabet AM, Wernig M, Südhof TC. Differential signaling mediated by ApoE2, ApoE3, and ApoE4 in human neurons parallels Alzheimer’s disease risk. J Neurosci. 2019;39:7408–27. 31331998 PMC6759032 · DOI · Paper page
  92. [111]Lessard CB, Malnik SL, Zhou Y, Ladd TB, Cruz PE, Ran Y, et al. High‐affinity interactions and signal transduction between Aβ oligomers and TREM 2. EMBO Mol Med. 2018;10:e9027. 30341064 PMC6220267 · DOI
  93. [112]Wang S, Sudan R, Peng V, Zhou Y, Du S, Yuede CM, et al. TREM2 drives microglia response to amyloid-β via SYK-dependent and-independent pathways. Cell. 2022;185:4153–69. e4119. 36306735 PMC9625082 · DOI · Paper page
  94. [113]Peng X, Guo H, Zhang X, Yang Z, Ruganzu JB, Yang Z, et al. TREM2 inhibits tau hyperphosphorylation and neuronal apoptosis via the PI3K/Akt/GSK-3β signaling pathway in vivo and in vitro. Mol Neurobiol. 2023;60:2470–85. 36662361 · DOI
  95. [114]Lin D, Kaye S, Chen M, Lyanna A, Ye L, Hammond LA, et al. Transcriptome and proteome profiling reveals TREM2-dependent and-independent glial response and metabolic perturbation in an Alzheimer’s mouse model. J Biol Chem. 2024;300:107874. 39395805 PMC11570940 · DOI
  96. [115]Sharoar MG, Hu X, Ma X-M, Zhu X, Yan R. Sequential formation of different layers of dystrophic neurites in Alzheimer’s brains. Mol Psychiatry. 2019;24:1369–82. 30899091 PMC7204504 · DOI · Paper page
  97. [118]Das T, Suman S, Alatassi H, Ankem M, Damodaran C. Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer. Cell Death Dis. 2016;7:e2111. 26913603 PMC4849149 · DOI
  98. [119]Omorou M, Huang Y, Gao M, Mu C, Xu W, Han Y, et al. The forkhead box O3 (FOXO3): a key player in the regulation of ischemia and reperfusion injury. Cell Mol Life Sci. 2023;80:102. 36939886 PMC11072419 · DOI
  99. [120]Deng Y, Ma G, Gao F, Sun X, Liu L, Mo D, et al. SOX9 knockdown-mediated FOXO3 downregulation confers neuroprotection against ischemic brain injury. Front Cell Dev Biol. 2021;8:555175. 33791290 PMC8006459 · DOI
  100. [121]Meng L, Feng B, Luan L, Fang Z, Zhao G. MeCP2 inhibits ischemic neuronal injury by enhancing methylation of the FOXO3a promoter to repress the SPRY2-ZEB1 axis. Exp Mol Med. 2022;54:1076–85. 35915222 PMC9440071 · DOI
  101. [122]Ruganzu JB, Peng X, He Y, Wu X, Zheng Q, Ding B, et al. Downregulation of TREM2 expression exacerbates neuroinflammatory responses through TLR4-mediated MAPK signaling pathway in a transgenic mouse model of Alzheimer’s disease. Mol Immunol. 2022;142:22–36. 34959070 · DOI
  102. [123]Zhang L, Liu Y, Wang X, Wang D, Wu H, Chen H, et al. Treadmill exercise improve recognition memory by TREM2 pathway to inhibit hippocampal microglial activation and neuroinflammation in Alzheimer’s disease model. Physiol Behav. 2022;251:113820. 35452628 · DOI
  103. [124]Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368:117–27. 23150934 PMC3631573 · DOI · Paper page
  104. [125]Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368:107–16. 23150908 PMC3677583 · DOI · Paper page
  105. [126]Iguchi A, Takatori S, Kimura S, Muneto H, Wang K, Etani H, et al. INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model. Iscience. 2023;26:106375. 37035000 PMC10074152 · DOI · Paper page
  106. [130]Jain N, Lewis CA, Ulrich JD, Holtzman DM. Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading. J Exp Med. 2022;220:e20220654. 36219197 PMC9559604 · DOI · Paper page
  107. [132]Leyns CE, Gratuze M, Narasimhan S, Jain N, Koscal LJ, Jiang H, et al. TREM2 function impedes tau seeding in neuritic plaques. Nat Neurosci. 2019;22:1217–22. 31235932 PMC6660358 · DOI · Paper page
  108. [133]Gratuze M, Schlachetzki JC, Albanus RDO, Jain N, Novotny B, Brase L, et al. TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4. Neuron. 2023;111:202–19.e207. 36368315 PMC9852006 · DOI · Paper page
  109. [134]Nabizadeh F, Seyedmirzaei H, Karami S. Neuroimaging biomarkers and CSF sTREM2 levels in Alzheimer’s disease: A longitudinal study. Sci Rep. 2024;14:15318. 38961148 PMC11222555 · DOI
  110. [135]Wang YC, Huang LY, Guo HH, Liu M, Zhang YY, Zhang ZQ, et al. Higher CSF sTREM2 attenuates APOE ε4‐related risk for amyloid pathology in cognitively intact adults: The CABLE study. J Neurochem. 2025;169:e16273. 39725857 · DOI
  111. [136]Zhao N, Qiao W, Li F, Ren Y, Zheng J, Martens YA, et al. Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia. J Exp Med. 2022;219:e20212479. 36107206 PMC9481739 · DOI
  112. [138]Zhao C, Qi W, Lv X, Gao X, Liu C, Zheng S. Elucidating the Role of Trem2 in Lipid Metabolism and Neuroinflammation. CNS Neurosci Ther. 2025;31:e70338. 40205810 PMC11982525 · DOI
  113. [139]Wei W, Zhang L, Xin W, Pan Y, Tatenhorst L, Hao Z, et al. TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury. Biomed Pharmacother. 2024;170:115962. 38042110 · DOI · Paper page
  114. [141]Vargas JY, Grudina C, Zurzolo C. The prion-like spreading of α-synuclein: From in vitro to in vivo models of Parkinson’s disease. Ageing Res Rev. 2019;50:89–101. 30690184 · DOI
  115. [142]Recchia A, Debetto P, Negro A, Guidolin D, Skaper SD, Giusti P. α‐Synuclein and Parkinson’s disease. FASEB J. 2004;18:617–26. 15054084 · DOI
  116. [143]Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K. The role of α-synuclein in Parkinson’s disease: insights from animal models. Nat Rev Neurosci. 2003;4:727–38. 12951565 · DOI
  117. [144]Stefanis L. α-Synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2:a009399. 22355802 PMC3281589 · DOI · Paper page
  118. [146]Castillo-Rangel C, Marin G, Hernandez-Contreras KA, Vichi-Ramirez MM, Zarate-Calderon C, Torres-Pineda O, et al. Neuroinflammation in Parkinson’s disease: From gene to clinic: a systematic review. Int J Mol Sci. 2023;24:5792. 36982866 PMC10051221 · DOI
  119. [147]Lauretti E, Praticò D. Circadian clock disruption and neuroinflammation in Parkinson’s disease: a new perspective. Genetics, Neurology, Behavior, and Diet in Parkinson’s Disease. Elsevier; 2020. p. 345–62.
  120. [149]Babkina I, Sergeeva S, Gorbacheva L. The role of NF-κB in neuroinflammation. Neurochem J. 2021;15:114–28. · DOI
  121. [150]Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. J Clin Invest. 2001;107:7–11. 11134171 PMC198552 · DOI · Paper page
  122. [151]Li Y, Zhang H, Kosturakis AK, Cassidy RM, Zhang H, Kennamer-Chapman RM, et al. MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy. Brain Behav Immun. 2015;49:255–66. 26065826 PMC4567501 · DOI
  123. [152]Minden A, Karin M. Regulation and function of the JNK subgroup of MAP kinases. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 1997;1333:F85–F104. 9395283 · DOI
  124. [153]Davis RJ. MAPKs: new JNK expands the group. Trends Biochem Sci. 1994;19:470–3. 7855889 · DOI
  125. [154]Chiu R, Boyle WJ, Meek J, Smeal T, Hunter T, Karin M. The c-fos protein interacts with c-JunAP-1 to stimulate transcription of AP-1 responsive genes. Cell. 1988;54:541–52. 3135940 · DOI
  126. [155]Huang P, Zhang Z, Zhang P, Feng J, Xie J, Zheng Y, et al. TREM2 deficiency aggravates NLRP3 inflammasome activation and pyroptosis in MPTP-induced Parkinson’s disease mice and LPS-induced BV2 cells. Mol Neurobiol. 2024;61:2590–605. 37917301 PMC11043123 · DOI · Paper page
  127. [156]Wang Z, Zhang S, Xiao Y, Zhang W, Wu S, Qin T, et al. NLRP3 inflammasome and inflammatory diseases. Oxid Med Cell Longev. 2020;2020:4063562. 32148650 PMC7049400
  128. [157]Milner MT, Maddugoda M, Götz J, Burgener SS, Schroder K. The NLRP3 inflammasome triggers sterile neuroinflammation and Alzheimer’s disease. Curr Opin Immunol. 2021;68:116–24. 33181351 · DOI
  129. [158]Shen H, Guan Q, Zhang X, Yuan C, Tan Z, Zhai L, et al. New mechanism of neuroinflammation in Alzheimer’s disease: the activation of NLRP3 inflammasome mediated by gut microbiota. Prog Neuro-Psychopharmacol Biol Psychiatry. 2020;100:109884. 32032696 · DOI
  130. [159]Han Q-Q, Le W. NLRP3 inflammasome-mediated neuroinflammation and related mitochondrial impairment in Parkinson’s disease. Neurosci Bull. 2023;39:832–44. 36757612 PMC10169990 · DOI
  131. [160]Yang S-J, Shao G-F, Chen J-L, Gong J. The NLRP3 inflammasome: an important driver of neuroinflammation in hemorrhagic stroke. Cell Mol Neurobiol. 2018;38:595–603. 28752408 PMC11481835 · DOI
  132. [161]Qin Q, Wan H, Wang D, Li J, Qu Y, Zhao J, et al. The association of CSF sTREM2 with cognitive decline and its dynamic change in Parkinson’s disease: analysis of the PPMI cohort. Front Aging Neurosci. 2022;14:892493. 35783125 PMC9245456 · DOI

Authors
Abdulkhaliq, A. A., Alasiri, G., Kim, B., Khan, J., Ajoolabady, A., Yousof, S. M., Ren, J., Tuomilehto, J., Borai, A., Alrfaei, B. M., & Pratico, D.
Affiliations
  • Umm al-Qura University (SA)
  • Imam Mohammad ibn Saud Islamic University (SA)
  • Kyung Hee University (KR)
  • Majmaah University (SA)
  • Fudan University (CN)
  • Suez Canal University (EG)
  • Finnish Institute for Health and Welfare (FI)
  • King Saud bin Abdulaziz University for Health Sciences (SA)
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2026-03-06
Volume
31
Issue
7
Pages
3978-3986
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-026-03505-7
PMC
PMC13268972
OpenAlex
W7134033067
Cited by
16
References
155
Citations by year
2026: 16
FWCI
12.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
Majmaah University
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords
TREM2, microglia, neuroinflammation, neurodegeneration, Alzheimer's disease, Parkinson's disease, microglial activation, neurodegenerative disease therapeutics
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Animals, Central Nervous System, Humans, Inflammation, Membrane Glycoproteins, Parkinson Disease, Receptors, Immunologic, Signal Transduction, Microglia, Neurodegenerative Diseases

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