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The orchestrating role of deteriorating neurons and TREM-1 in crosstalk with SYK in Alzheimer’s disease progression and neuroinflammation

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Abstract

Alzheimer’s disease (AD) is a progressive type of neurodegenerative disease characterized by successive loss of the conventional structure and functions of neurons. In addition to dead neurons type detected within AD brain tissues, there are a predominantly varying number of deteriorating neurons (DTNs). As the number of deteriorating neurons increases, they exaggerate the release of inflammatory factors and oxidative stress that trigger the cascade of neuroinflammation. Triggering receptor expressed on myeloid cells 1 (TREM-1) which is a transmembrane immune receptor type regularly expressed by phagocytic cells, may act as a stimulating factor for neuroinflammation. Once TREM-1 is activated, it directly activates spleen tyrosine kinase (SYK) downstream signaling cascades, which can be considered an initiating phase for AD pathology and AD progression. Sequentially, SYK activates the pro-inflammatory microglia M1 phenotype which executes several inflammatory actions, leading to neurotoxicity. These released neurotoxins promote neuronal cell death, synaptic dysfunctions, and memory impairments. Thus, the current review outlines the direct etiological and pathologic features of Alzheimer’s disease linked with deteriorating neurons, TREM-1, and SYK.

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No data were used for the research described in the article.

Abbreviations

AD:

Alzheimer’s disease

DTNs:

Deteriorating neurons

TREM-1:

Triggering receptor expressed on myeloid cells 1

SYK:

Spleen tyrosine kinase (SYK)

LOAD:

Late-onset type of AD

NF-κB:

Nuclear factor kappa B

CBF:

Cerebral blood flow

MAP kinase:

Mitogen-activated protein kinase

TNF-α:

Tumor necrosis factor-alpha

IL-6:

Interleukin 6

TLR-4:

Toll-like receptor

PTK:

Protein–tyrosine kinase

PI3K:

Phosphoinositide 3-kinase

JAK:

Janus kinase

GSK3β:

Glycogen Synthase Kinase 3 Beta

NLRP3:

NOD-, LRR- and pyrin domain-containing protein 3

DAP12:

DNAX activation protein of 12 kDa

PLCγ:

Phosphoinositide phospholipase C-gamma

PRRs:

Pattern recognition receptors

MyD88:

Myeloid differentiation factor 88

BACE1:

Beta-secretase

References

  • Alsop DC, Detre JA, Grossman M (2000) Assessment of cerebral blood flow in Alzheimer’s disease by spin-labeled magnetic resonance imaging. Ann Neurol 47:93–100

    Article  CAS  PubMed  Google Scholar 

  • Anwar M, Fathi M (2022) The cross-talk between microglia-derived exosomes and brain printing biometrics as a diagnostic approach for Parkinson’s disease prior to motor symptoms implications [abstract]. Mov Disord 37(S2):S647–S648

    Google Scholar 

  • Anwar MM (2021a) Brain-printing biometrics underlying mechanism as an early diagnostic technique for Alzheimer’s disease neurodegenerative type. Curr Res Physiol 4:216–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anwar MM (2021b) Oxidative stress-A direct bridge to central nervous system homeostatic dysfunction and Alzheimer’s disease. Cell Biochem Funct. https://doi.org/10.1002/cbf.3673

    Article  PubMed  Google Scholar 

  • Anwar MM, Fathi MH (2023) Early approaches of YKL-40 as a biomarker and therapeutic target for Parkinson’s disease. Neurodegener Dis Manag. https://doi.org/10.2217/nmt-2022-0010

    Article  PubMed  Google Scholar 

  • Anwar MM, Mabrouk AA (2023) Hepatic and cardiac implications of increased toxic amyloid-beta serum level in lipopolysaccharide-induced neuroinflammation in rats: new insights into alleviating therapeutic interventions. Inflammopharmacology. https://doi.org/10.1007/s10787-023-01202-3

    Article  PubMed  PubMed Central  Google Scholar 

  • Anwar MM, Ali OS, Rashed LA, Badawi AM, Eltablawy NA (2018) Regulation of miRNA-124, nuclear factor-kappa B and β-catenin expression in response to novel therapeutic protocol in LPS induced Alzheimer’s disease in rats. Res Neurosci 7:17

    Google Scholar 

  • Anwar MM, Ali OS, Rashed LA, Badawi AM, Eltablawy NA (2019) The neuro engraftment and neuroregenerative effects of hydrogen sulphide donor, intracerebral MSCs, Ginko Biloba and Kefir in attenuating neuropathological hallmarks of lipopolysaccharide induced Alzheimer’s disease rat models. Int J Aging Res 2:38

    Google Scholar 

  • Anwar MM, Özkan E, Gürsoy-Özdemir Y (2021) The role of extracellular matrix alterations in mediating astrocyte damage and pericyte dysfunction in Alzheimer’s disease: a comprehensive review. Eur J Neurosci. https://doi.org/10.1111/ejn.15372

    Article  PubMed  Google Scholar 

  • Anwar MM, Özkan E, Shomalizadeh N, Sapanci S, Özler C, Kesibi J, Gürsoy-Özdemir Y (2023) Assessing the role of primary healthy microglia and gap junction blocker in hindering Alzheimer’s disease neuroinflammatory type: Early approaches for therapeutic intervention. Front Neurosci. https://doi.org/10.3389/fnins.2022.1041461

    Article  PubMed  PubMed Central  Google Scholar 

  • Aoki N, Kimura S, Xing Z (2003) Role of DAP12 in innate and adaptive immune responses. Curr Pharm Des 9:7–10

    Article  CAS  PubMed  Google Scholar 

  • Association AS (2019) 2019 Alzheimer’s disease facts and figures. Alzheimers Dement 15:321–387

    Article  Google Scholar 

  • Birkle TJY, Brown GC (2023) Syk inhibitors protect against microglia-mediated neuronal loss in culture. Front Aging Neurosci 15:1120952

    Article  PubMed  PubMed Central  Google Scholar 

  • Chaplin DD (2010) Overview of the immune response. J Allergy Clin Immunol 125:S3-23

    Article  PubMed  PubMed Central  Google Scholar 

  • Colonna M (2003) TREMs in the immune system and beyond. Nat Rev Immunol 3:445–453

    Article  CAS  PubMed  Google Scholar 

  • de Oliveira Matos A, dos Santos Dantas PH, Silva-Sales FM, Sales-Campos H (2020) The role of the triggering receptor expressed on myeloid cells-1 (TREM-1) in non-bacterial infections. Crit Rev Microbiol 46:237–252

    Article  PubMed  Google Scholar 

  • de Oliveira Matos A, dos Santos Dantas PH, Colmenares MTC, Sartori GR, Silva-Sales M, da Silva JHM, Neves BJ, Andrade CH, Sales-Campos H (2023) The CDR3 region as the major driver of TREM-1 interaction with its ligands, an in silico characterization. Comput Struct Biotechnol J 21:2579–2590

    Article  PubMed  PubMed Central  Google Scholar 

  • Derkinderen P, Scales TM, Hanger DP, Leung KY, Byers HL, Ward MA, Lenz C, Price C, Bird IN, Perera T, Kellie S, Williamson R, Noble W, van Etten RA, Leroy K, Brion JP, Reynolds CH, Anderton BH (2005) Tyrosine 394 is phosphorylated in Alzheimer’s paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. J Neurosci 25:6584–6593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deture MA, Dickson DW (2019) The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 14:32

    Article  PubMed  PubMed Central  Google Scholar 

  • Faruki S, Geahlen RL, Asai DJ (2000) Syk-dependent phosphorylation of microtubules in activated B-lymphocytes. J Cell Sci 113(Pt 14):2557–2565

    Article  CAS  PubMed  Google Scholar 

  • Feng C-W, Chen N-F, Sung C-S, Kuo H-M, Yang S-N, Chen C-L, Hung H-C, Chen B-H, Wen Z-H, Chen W-F (2019) Therapeutic effect of modulating TREM-1 via anti-inflammation and autophagy in Parkinson’s disease. Front Neurosci 13:769

    Article  PubMed  PubMed Central  Google Scholar 

  • Fortin CF, Lesur O, Fulop T (2007) Effects of TREM-1 activation in human neutrophils: activation of signaling pathways, recruitment into lipid rafts and association with TLR4. Int Immunol 19:41–50

    Article  CAS  PubMed  Google Scholar 

  • Geahlen RL (2014) Getting Syk: spleen tyrosine kinase as a therapeutic target. Trends Pharmacol Sci 35:414–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldsmith HS (2014) Benefit of omental blood flow in Alzheimer’s disease: effect on deteriorating neurons. J Alzheimers Dis 42(Suppl 3):S277–S280

    Article  PubMed  Google Scholar 

  • Goldsmith HS (2022) Alzheimer’s disease: a decreased cerebral blood flow to critical intraneuronal elements is the cause. J Alzheimers Dis 85:1419–1422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He X, Huang Y, Liu Y, Zhang X, Yue P, Ma X, Miao Z, Long X, Yang Y, Wan X, Lei J, Shu K, Lei T, Gan C, Zhang H (2022) BAY61-3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury. Int J Mol Med 49:1–3

    Google Scholar 

  • Kapasouri EM, Ioannidis DC, Cameron D, Vassiliou VS, Hornberger M (2022) The utility of arterial spin labeling MRI in medial temporal lobe as a vascular biomarker in Alzheimer’s disease spectrum: a systematic review and meta-analysis. Diagnostics 12:2967

    Article  PubMed  PubMed Central  Google Scholar 

  • Kelker MS, Foss TR, Peti W, Teyton L, Kelly JW, Wüthrich K, Wilson IA (2004) Crystal structure of human triggering receptor expressed on myeloid cells 1 (TREM-1) at 1.47 A. J Mol Biol 342:1237–1248

    Article  CAS  PubMed  Google Scholar 

  • Kim MW, Choe K (2022) Pharmacological inhibition of spleen tyrosine kinase suppressed neuroinflammation and cognitive dysfunction in LPS-induced neurodegeneration model. Cells 11:1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Z, Wu F, Xu D, Zhi Z, Xu G (2019) Inhibition of TREM1 reduces inflammation and oxidative stress after spinal cord injury (SCI) associated with HO-1 expressions. Biomed Pharmacother 109:2014–2021

    Article  CAS  PubMed  Google Scholar 

  • Marchetti G, Dessì A (2020) Syk inhibitors: new computational insights into their intraerythrocytic action in plasmodium falciparum malaria. Int J Mol Sci 21:7009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mcadoo SP, Tam FW (2011) Fostamatinib disodium. Drugs Fut 36:273

    Article  CAS  Google Scholar 

  • Paris D, Ait-Ghezala G, Bachmeier C, Laco G, Beaulieu-Abdelahad D, Lin Y, Jin C, Crawford F, Mullan M (2014) The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation. J Biol Chem 289:33927–33944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Radsak MP, Salih HR, Rammensee HG, Schild H (2004) Triggering receptor expressed on myeloid cells-1 in neutrophil inflammatory responses: differential regulation of activation and survival. J Immunol 172:4956–4963

    Article  CAS  PubMed  Google Scholar 

  • Roe K, Gibot S, Verma S (2014) Triggering receptor expressed on myeloid cells-1 (TREM-1): a new player in antiviral immunity? Front Microbiol 5:627

    Article  PubMed  PubMed Central  Google Scholar 

  • Ruzza P, Biondi B, Calderan A (2009) Therapeutic prospect of Syk inhibitors. Expert Opin Ther Pat 19:1361–1376

    Article  CAS  PubMed  Google Scholar 

  • Sagulenko V, Thygesen SJ, Sester DP, Idris A, Cridland JA, Vajjhala PR, Roberts TL, Schroder K, Vince JE, Hill JM, Silke J, Stacey KJ (2013) AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ 20:1149–1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sehar U, Rawat P, Reddy AP, Kopel J, Reddy PH (2022) Amyloid beta in aging and Alzheimer’s disease. Int J Mol Sci 23:12924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi X, Wei T, Hu Y, Wang M, Tang Y (2022) The associations between plasma soluble Trem1 and neurological diseases: a Mendelian randomization study. J Neuroinflammation 19:218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tessarz AS, Weiler S, Zanzinger K, Angelisová P, Horejsí V, Cerwenka A (2007) Non-T cell activation linker (NTAL) negatively regulates TREM-1/DAP12-induced inflammatory cytokine production in myeloid cells. J Immunol 178:1991–1999

    Article  CAS  PubMed  Google Scholar 

  • Tsuruga K, Sugawara N, Yasui-Furukori N, Takahashi I, Tsuchimine S, Kaneda A, Nakaji S, Nakamura K (2014) A positive correlation between serum amyloid β levels and depressive symptoms among community-dwelling elderly individuals in Japan. Neuropsychiatr Dis Treat 10:1621–1627

    PubMed  PubMed Central  Google Scholar 

  • Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, Vieira-Saecker A, Schwartz S, Santarelli F, Kummer MP, Griep A, Gelpi E, Beilharz M, Riedel D, Golenbock DT, Geyer M, Walter J, Latz E, Heneka MT (2017) Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552:355–361

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Zeng H, Xu C, Chen H, Fan L, Zhou H, Yu Q, Fu X, Peng Y, Yan F, Yu X, Chen G (2021) TREM1 regulates neuroinflammatory injury by modulate proinflammatory subtype transition of microglia and formation of neutrophil extracellular traps via interaction with SYK in experimental subarachnoid hemorrhage. Front Immunol. https://doi.org/10.3389/fimmu.2021.766178

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu P, Zhang X, Liu Q, Xie Y, Shi X, Chen J, Li Y, Guo H, Sun R, Hong Y, Liu X, Xu G (2019) Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke. Cell Death Dis 10:555

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi T, Hamano T, Sada K, Kanaan NM, Sasaki H, Yen S-H, Asano R, Enomoto S, Shirafuji N, Ueno A, Ikawa M, Yamamura O, Nakamoto Y (2020) Syk inhibitor reduces oligomeric tau associated with GSK3β inactivation and autophagy activation. Alzheimers Dement 16:e042633

    Article  Google Scholar 

  • Zhang C, Kan X, Zhang B, Ni H, Shao J (2022) The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases. Mol Brain 15:84

    Article  PubMed  PubMed Central  Google Scholar 

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  1. Department of Biochemistry, National Organization for Drug Control and Research (NODCAR), Egyptian Drug Authority (EDA), Cairo, Egypt

    Mai M. Anwar

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  1. Mai M. Anwar
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MMA organized the main ideas of the current review, finalized, and submitted the final version for review.

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Correspondence to Mai M. Anwar.

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Anwar, M.M. The orchestrating role of deteriorating neurons and TREM-1 in crosstalk with SYK in Alzheimer’s disease progression and neuroinflammation. Inflammopharmacol 31, 2303–2310 (2023). https://doi.org/10.1007/s10787-023-01270-5

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