Immune Signaling in Neurodegeneration

Hammond, Timothy R.; Marsh, Samuel E.; Stevens, Beth

doi:10.1016/j.immuni.2019.03.016

Cited by 336Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesAlzheimer's disease research and treatments

Immune Signaling in Neurodegeneration

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Hammond, Timothy R., Marsh, Samuel E., Stevens, Beth·2019·Immunity

DOI 10.1016/j.immuni.2019.03.016PMC PMC6822103

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Abstract

Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-β, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.

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AD pathology is characterized by extracellular amyloid plaques and intracellular NFTs surrounded by immune cells, especially microglia; clinical manifestation is progressive cognitive impairment.
“The pathology of AD is characterized by extracellular amyloid plaques and intracellular NFTs, which are surrounded by immune cells, especially microglia; the clinical manifestation of AD is characterized by progressive cognitive impairment.14”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [14]
The “Clinical & Pathological Characteristics of Neurodegenerative Disease” section describes extracellular amyloid-beta plaques, intracellular tau tangles, and progressive cognitive decline in AD. It places immune cells, likely microglia, close to plaques, but does not say they surround the tangles. (LLM, conf=0.86)
Experimental — accuracy not yet measured
The shared associations in chr6 region with both immunological and neurodegenerative traits adds evidence to the known relationship between these two processes.
“The shared associations in this region with both immunological and neurodegenerative traits adds evidence to the known relationship between these two processes36.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [36]
Aβ binds to microglial TREM2, activating TREM2 signaling and leading to enhanced phagocytosis.
“Aβ binds to microglial TREM2, which activates TREM2 signaling and lead to the enhanced phagocytosis of microglia.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [174]

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Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes
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“It was first cloned in 2000 by Marco Colonna and colleagues (Bouchon et al., 2000) and is part of a series of Trem and Trem-like genes on human chromosome 6 (mouse chr.”
Background
An environment-dependent transcriptional network specifies human microglia identity
Gosselin, D., Skola, D., Coufal, N. G., Holtman, I. R., Schlachetzki, J. C. M., Sajti, E., Jaeger, B. N., O’Connor, C., Fitzpatrick, C., Pasillas, M. P., et al. (2017) · Science · doi:10.1126/science.aal3222 · Cited by 1,220 · see citing works
Identification of Tim4 as a phosphatidylserine receptor
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Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease
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Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease
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iPSC-derived human microglia-like cells to study neurological diseases
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Self-citation
Frontotemporal dementia
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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
ARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,126 · cited 4× · see citing works
“More recently, rare variant analyses have also uncovered AD risk variants within the microglia-specific genes PLCG2 and ABI3 (Huang et al., 2017; Sims et al., 2017).”
BackgroundInfluential
Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2
Takahashi, K., Rochford, C. D. P., & Neumann, H. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041611 · Cited by 1,124 · see citing works
Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease
Giannakopoulos, P., Herrmann, F. R., Bussière, T., Bouras, C., Kövari, E., Perl, D. P., Morrison, J. H., Gold, G., & Hof, P. R. (2003) · Neurology · doi:10.1212/01.wnl.0000063311.58879.01 · Cited by 1,118 · see citing works
The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease
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Self-citation
A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci
Chang, D., Nalls, M. A., Hallgrímsdóttir, I. B., Hunkapiller, J., van der Brug, M., Cai, F., International Parkinson's Disease Genomics Consortium, 23andMe Research Team, Kerchner, G. A., Ayalon, G., et al. (2017) · Nature Genetics · doi:10.1038/ng.3955 · Cited by 1,112 · see citing works
Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice
Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., Smith, L. K., Bieri, G., Lin, K., Berdnik, D., et al. (2014) · Nature Medicine · doi:10.1038/nm.3569 · Cited by 1,081 · see citing works
Identification of two distinct synucleins from human brain
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Vascular and Neurogenic Rejuvenation of the Aging Mouse Brain by Young Systemic Factors
Katsimpardi, L., Litterman, N. K., Schein, P. A., Miller, C. M., Loffredo, F. S., Wojtkiewicz, G. R., Chen, J. W., Lee, R. T., Wagers, A. J., & Rubin, L. L. (2014) · Science · doi:10.1126/science.1251141 · Cited by 1,037 · see citing works
Clinical progression in Parkinson disease and the neurobiology of axons
Cheng, H., Ulane, C. M., & Burke, R. E. (2010) · Annals of Neurology · doi:10.1002/ana.21995 · Cited by 1,012 · cited 1× · see citing works
“The onset of symptoms follows significant loss of dopamine-producing neurons in the substantia nigra that appears to accelerate exponentially as the disease progresses (Cheng et al., 2010; Greffard et al., 2006).”
Background
The complement system
Sarma, J. V., & Ward, P. A. (2010) · Cell and Tissue Research · doi:10.1007/s00441-010-1034-0 · Cited by 988 · see citing works
TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943 · see citing works
T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Sulzer, D., Alcalay, R. N., Garretti, F., Cote, L., Kanter, E., Agin-Liebes, J., Liong, C., McMurtrey, C., Hildebrand, W. H., Mao, X., et al. (2017) · Nature · doi:10.1038/nature22815 · Cited by 866 · see citing works
TGF-β Activation and Function in Immunity
Travis, M. A., & Sheppard, D. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120257 · Cited by 856 · see citing works
BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module
Park, D., Tosello‐Trampont, A., Elliott, M. R., Lu, M., Haney, L. B., Ma, Z., Klibanov, A. L., Mandell, J. W., & Ravichandran, K. S. (2007) · Nature · doi:10.1038/nature06329 · Cited by 848 · see citing works
Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR
McGeer, P. L., Itagaki, S., Tago, H., & McGeer, E. G. (1987) · Neuroscience Letters · doi:10.1016/0304-3940(87)90696-3 · Cited by 836 · see citing works
TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.003 · Cited by 817 · see citing works
Complement activation by beta-amyloid in Alzheimer disease.
Rogers, J., Cooper, N. R., Webster, S., Schultz, J., McGeer, P. L., Styren, S. D., Civin, W. H., Brachova, L., Bradt, B., & Ward, P. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.21.10016 · Cited by 817 · see citing works
Tau and neurodegenerative disease: the story so far
Iqbal, K., Liu, F., & Gong, C.-X. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.225 · Cited by 806 · see citing works
Regulation of learning and memory by meningeal immunity: a key role for IL-4
Derecki, N. C., Cardani, A. N., Yang, C. H., Quinnies, K. M., Crihfield, A., Lynch, K. R., & Kipnis, J. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20091419 · Cited by 800 · see citing works
APP mouse models for Alzheimer’s disease preclinical studies.
Sasaguri, H., Nilsson, P., Hashimoto, S., Nagata, K., Saito, T., De Strooper, B., Hardy, J., Vassar, R., Winblad, B., & Saido, T. C. (2017) · The EMBO Journal · doi:10.15252/embj.201797397 · Cited by 793 · see citing works
Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease.
Köpke, E., Tung, Y. C., Shaikh, S., Alonso, A. C., Iqbal, K., & Grundke-Iqbal, I. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80536-5 · Cited by 779 · see citing works
Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease
Hamza, T. H., Zabetian, C. P., Tenesa, A., Laederach, A., Montimurro, J. S., Yearout, D., Kay, D. M., Doheny, K. F., Paschall, J. E., Pugh, E., et al. (2010) · Nature Genetics · doi:10.1038/ng.642 · Cited by 779 · see citing works
TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function
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. (2018) · Neuron · doi:10.1016/j.neuron.2018.01.031 · Cited by 763 · see citing works
The A4 Study: Stopping AD Before Symptoms Begin?
Sperling, R. A., Rentz, D. M., Johnson, K. A., Karlawish, J. H., Donohue, M., Salmon, D. P., & Aisen, P. S. S. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007941 · Cited by 756 · see citing works
Lewy Bodies in Alzheimer's Disease: A Neuropathological Review of 145 Cases Using α‐Synuclein Immunohistochemistry
Hamilton, R. L. (2000) · Brain Pathology · doi:10.1111/j.1750-3639.2000.tb00269.x · Cited by 754 · see citing works
Brain homogenates from human tauopathies induce tau inclusions in mouse brain
Clavaguera, F., Akatsu, H., Fraser, G. M., Crowther, R. A., Frank, S., Hench, J., Probst, A., Winkler, D. T., Reichwald, J., Staufenbiel, M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301175110 · Cited by 750 · see citing works
Expression of immune system-associated antigens by cells of the human central nervous system: Relationship to the pathology of Alzheimer's disease
Rogers, J., Luber-Narod, J., Styren, S. D., & Civin, W. H. (1988) · Neurobiology of Aging · doi:10.1016/s0197-4580(88)80079-4 · Cited by 743 · see citing works
Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution
Mathys, H., Adaikkan, C., Gao, F., Young, J. Z., Manet, E., Hemberg, M., De Jager, P. L., Ransohoff, R. M., Regev, A., & Tsai, L.-H. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.039 · Cited by 740 · see citing works
TREM2 — a key player in microglial biology and Alzheimer disease
Ulland, T. K., & Colonna, M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0072-1 · Cited by 735 · see citing works
Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation
Lui, H., Zhang, J., Makinson, S. R., Cahill, M. K., Kelley, K. W., Huang, H.-Y., Shang, Y., Oldham, M. C., Martens, L. H., Gao, F., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.001 · Cited by 729 · see citing works
Mutations in Two Genes Encoding Different Subunits of a Receptor Signaling Complex Result in an Identical Disease Phenotype
Paloneva, J., Manninen, T., Christman, G., Hovanes, K., Mandelin, J., Adolfsson, R., Bianchin, M., Bird, T., Miranda, R., Salmaggi, A., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/342259 · Cited by 683 · see citing works
TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models
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. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142322 · Cited by 682 · cited 1× · see citing works
“In line with the model of TREM2 as a sensor is the consistent finding that in amyloid mouse models crossed to Trem2-KO mice microglia no longer cluster in close proximity to amyloid plaques (Jay et al., 2015; Wang et al., 2015; Yuan et al., 2016).”
Genetics of global gene expression
Rockman, M. V., & Kruglyak, L. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1964 · Cited by 666 · cited 1× · see citing works
“Researchers have used GWASs and genotyping results combined with gene expression data to perform an analysis of expression quantitative trait loci (eQTLs), to determine whether a single nucleotide polymorphism (SNP) from a GWAS is associated with altered expression of either local (cis-eQTL) or distant (trans-eQTL) ge…”
Method
Microglia Modulate Wiring of the Embryonic Forebrain
Squarzoni, P., Oller, G., Hoeffel, G., Pont‐Lezica, L., Rostaing, P., Low, D., Bessis, A., Ginhoux, F., & Garel, S. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.042 · Cited by 655 · see citing works
Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer's disease.
Jawhar, S., Trawicka, A., Jenneckens, C., Bayer, T. A., & Wirths, O. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.05.027 · Cited by 623 · cited 2× · see citing works
“Transgenic expression of the mutated forms of the human genes leads to toxic oligomeric Ab accumulation and plaque formation (Games et al., 1995; Hsiao et al., 1996; Jawhar et al., 2012; Oakley et al., 2006).”
Background
Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease
Jones, L., Holmans, P. A., Hamshere, M. L., Harold, D., Moskvina, V., Ivanov, D., Pocklington, A., Abraham, R., Hollingworth, P., Sims, R., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013950 · Cited by 606 · see citing works
Lewy body dementias
Walker, Z., Possin, K. L., Boeve, B. F., & Aarsland, D. (2015) · The Lancet · doi:10.1016/s0140-6736(15)00462-6 · Cited by 605 · see citing works
Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease
Lian, H., Litvinchuk, A., Chiang, A. C.-A., Aithmitti, N., Jankowsky, J. L., & Zheng, H. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.2117-15.2016 · Cited by 597 · see citing works
Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice
Shi, Q., Chowdhury, S., Ma, R., Le, K. X., Hong, S., Caldarone, B. J., Stevens, B., & Lemere, C. A. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf6295 · Cited by 593 · cited 3× · see citing works
“It is becoming increasingly clear that microglia and immune signaling may not just be secondary players in disease processes but actually contribute to synaptic and neuron loss and buildup of pathogenic proteins even at the earliest stages of disease (Figure 2) (Hong et al., 2016; Shi et al., 2017; Sosna et al., 2018).”
BackgroundSelf-citation
Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679043 · Cited by 587 · see citing works
TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice
Wyss-Coray, T., Lin, C., Yan, F., Yu, G.-Q., Rohde, M., McConlogue, L., Masliah, E., & Mucke, L. (2001) · Nature Medicine · doi:10.1038/87945 · Cited by 587 · see citing works
Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
Van Deerlin, V. M., Sleiman, P. M. A., Martinez-Lage, M., Chen-Plotkin, A., Wang, L.-S., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Grossman, M., et al. (2010) · Nature Genetics · doi:10.1038/ng.536 · Cited by 579 · see citing works
Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease
Gjoneska, E., Pfenning, A. R., Mathys, H., Quon, G., Kundaje, A., Tsai, L.-H., & Kellis, M. (2015) · Nature · doi:10.1038/nature14252 · Cited by 576 · see citing works
Animal models of neurodegenerative diseases
Dawson, T. M., Golde, T. E., & Lagier-Tourenne, C. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0236-8 · Cited by 576 · see citing works
Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies
Dejanovic, B., Huntley, M. A., De Mazière, A., Meilandt, W. J., Wu, T., Srinivasan, K., Jiang, Z., Gandham, V., Friedman, B. A., Ngu, H., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.014 · Cited by 575 · see citing works
GWAS on family history of Alzheimer’s disease
Marioni, R. E., Harris, S. E., Zhang, Q., McRae, A. F., Hagenaars, S. P., Hill, W. D., Davies, G., Ritchie, C. W., Gale, C. R., Starr, J. M., et al. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0150-6 · Cited by 564 · see citing works
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0296-9 · Cited by 555 · see citing works
A combination of ontogeny and CNS environment establishes microglial identity
Bennett, F. C., Bennett, M. L., Yaqoob, F., Mulinyawe, S. B., Grant, G. A., Hayden Gephart, M., Plowey, E. D., & Barres, B. A. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.014 · Cited by 524 · see citing works
Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease
Litvinchuk, A., Wan, Y.-W., Swartzlander, D. B., Chen, F., Cole, A., Propson, N. E., Wang, Q., Zhang, B., Liu, Z., & Zheng, H. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.031 · Cited by 523 · see citing works
Current state of Alzheimer’s fluid biomarkers
Molinuevo, J. L., Ayton, S., Batrla, R., Bednar, M. M., Bittner, T., Cummings, J., Fagan, A. M., Hampel, H., Mielke, M. M., Mikulskis, A., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1932-x · Cited by 518 · see citing works
TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy
Leyns, C. E. G., Ulrich, J. D., Finn, M. B., Stewart, F. R., Koscal, L. J., Remolina Serrano, J., Robinson, G. O., Anderson, E., Colonna, M., & Holtzman, D. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710311114 · Cited by 517 · cited 1× · see citing works
“While one report found that Trem2-KO reduced brain atrophy but had no impact on tau pathology when crossed to the PS19 transgenic tau model (Leyns et al., 2017), another report found that a different Trem2-KO mouse crossed with a different tau model exacerbated tau pathology (Bemiller et al.”
Background
Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes
Raj, T., Rothamel, K., Mostafavi, S., Ye, C., Lee, M. N., Replogle, J. M., Feng, T., Lee, M., Asinovski, N., Frohlich, I., et al. (2014) · Science · doi:10.1126/science.1249547 · Cited by 506 · see citing works
Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology
Baruch, K., Rosenzweig, N., Kertser, A., Deczkowska, A., Sharif, A. M., Spinrad, A., Tsitsou-Kampeli, A., Sarel, A., Cahalon, L., & Schwartz, M. (2015) · Nature Communications · doi:10.1038/ncomms8967 · Cited by 491 · see citing works
Motor symptoms in Parkinson’s disease: A unified framework
Moustafa, A. A., Chakravarthy, V. S., Phillips, J. R., Gupta, A., Kéri, S., Polner, B., Frank, M. J., & Jahanshahi, M. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.07.010 · Cited by 485 · see citing works
A Guide to Neurotoxic Animal Models of Parkinson's Disease
Tieu, K. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009316 · Cited by 483 · see citing works
MPTP Mouse Models of Parkinson’s Disease: An Update
Meredith, G. E., & Rademacher, D. J. (2011) · Journal of Parkinson's Disease · doi:10.3233/jpd-2011-11023 · Cited by 471 · see citing works
Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo
Kaufman, S. K., Sanders, D. W., Thomas, T. L., Ruchinskas, A. J., Vaquer-Alicea, J., Sharma, A. M., Miller, T. M., & Diamond, M. I. (2016) · Neuron · doi:10.1016/j.neuron.2016.09.055 · Cited by 450 · see citing works
Human umbilical cord plasma proteins revitalize hippocampal function in aged mice
Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., Shen, J. C., Zou, B., Xie, X. S., Tingle, M., et al. (2017) · Nature · doi:10.1038/nature22067 · Cited by 445 · see citing works
TREM2, microglia, and neurodegenerative diseases
Yeh, F. L., Hansen, D. V., & Sheng, M. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.008 · Cited by 440 · cited 3× · see citing works
“Activation of TREM2 downstream signaling results in a number of different cellular effector functions including alterations in proliferation, altered survival, cytokine release, phagocytosis, and migration (for review see (Kober and Brett, 2017; Ulland and Colonna, 2018; Yeh et al., 2017)).”
BackgroundResult
A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease
The International Genomics of Alzheimer's Project, Huang, K.-L., Initiative, T. A. D. N., Marcora, E., Pimenova, A. A., Di Narzo, A. F., Kapoor, M., Jin, S. C., Harari, O., Bertelsen, S., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4587 · Cited by 423 · see citing works
A Dramatic Increase of C1q Protein in the CNS during Normal Aging
Stephan, A. H., Madison, D. V., Mateos, J. M., Fraser, D. A., Lovelett, E. A., Coutellier, L., Kim, L., Tsai, H.-H., Huang, E. J., Rowitch, D. H., et al. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1333-13.2013 · Cited by 423 · see citing works
TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1
Peng, Q., Malhotra, S., Torchia, J. A., Kerr, W. G., Coggeshall, K. M., & Humphrey, M. B. (2010) · Science Signaling · doi:10.1126/scisignal.2000500 · Cited by 413 · see citing works
Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia
Cronk, J. C., Filiano, A. J., Louveau, A., Marin, I., Marsh, R., Ji, E., Goldman, D. H., Smirnov, I., Geraci, N., Acton, S., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180247 · Cited by 412 · see citing works
The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function
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. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525466113 · Cited by 411 · see citing works
Self-citation
Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease
Sosna, J., Philipp, S., Albay, R., Reyes-Ruiz, J. M., Baglietto-Vargas, D., LaFerla, F. M., & Glabe, C. G. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0244-x · Cited by 406 · see citing works
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Dementia with Lewy bodies: an update and outlook
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APOE ϵ4 Increases Risk for Dementia in Pure Synucleinopathies
Tsuang, D., Leverenz, J. B., Lopez, O. L., Hamilton, R. L., Bennett, D. A., Schneider, J. A., Buchman, A. S., Larson, E. B., Crane, P. K., Kaye, J. A., et al. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.600 · Cited by 378 · see citing works
Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement
Guerreiro, R. J., Lohmann, E., Brás, J. M., Gibbs, J. R., Rohrer, J. D., Gurunlian, N., Dursun, B., Bilgic, B., Hanagasi, H., Gurvit, H., et al. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.579 · Cited by 374 · see citing works
Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs
Mócsai, A., Abram, C. L., Jakus, Z., Hu, Y., Lanier, L. L., & Lowell, C. A. (2006) · Nature Immunology · doi:10.1038/ni1407 · Cited by 369 · see citing works
Enhanced synaptic connectivity and epilepsy in C1q knockout mice
Chu, Y., Jin, X., Parada, I., Pesic, A., Stevens, B., Barres, B., & Prince, D. A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913449107 · Cited by 364 · see citing works
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Soluble TREM2 induces inflammatory responses and enhances microglial survival
Zhong, L., Chen, X., Wang, T., Wang, Z., Liao, C., Wang, Z., Huang, R., Wang, D., Li, X., Wu, L., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160844 · Cited by 358 · see citing works
Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology
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Motor Score of the Unified Parkinson Disease Rating Scale as a Good Predictor of Lewy Body–Associated Neuronal Loss in the Substantia Nigra
Greffard, S., Verny, M., Bonnet, A.-M., Beinis, J., Gallinari, C., Meaume, S., Piette, F., Hauw, J., & Duyckaerts, C. J. (2006) · Archives of Neurology · doi:10.1001/archneur.63.4.584 · Cited by 355 · see citing works
Early increase of CSF sTREM2 in Alzheimer’s disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
Initiative, F. T. A. D. N., Suárez-Calvet, M., Morenas-Rodríguez, E., Kleinberger, G., Schlepckow, K., Araque Caballero, M. Á., Franzmeier, N., Capell, A., Fellerer, K., Nuscher, B., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0301-5 · Cited by 347 · see citing works
Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status
Piccio, L., Deming, Y., Del-Águila, J. L., Ghezzi, L., Holtzman, D. M., Fagan, A. M., Fenoglio, C., Galimberti, D., Borroni, B., & Cruchaga, C. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1533-5 · Cited by 337 · see citing works
beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain.
Jiang, H., Burdick, D., Glabe, C. G., Cotman, C. W., & Tenner, A. J. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.152.10.5050 · Cited by 330 · cited 1× · see citing works
“C1q binds to Aβ and is localized to plaques in AD patients and in APP mouse models (Afagh et al., 1996; Jiang et al., 1994; Reichwald et al., 2009; Rogers et al., 1992) (Figure 3B).”
Background
Up-Regulated Production and Activation of the Complement System in Alzheimer's Disease Brain
Yasojima, K., Schwab, C., McGeer, E. G., & McGeer, P. L. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65340-0 · Cited by 328 · see citing works
Loss of TGF-β1 Leads to Increased Neuronal Cell Death and Microgliosis in Mouse Brain
Brionne, T. C., Tesseur, I., Masliah, E., & Wyss-Coray, T. (2003) · Neuron · doi:10.1016/s0896-6273(03)00766-9 · Cited by 325 · see citing works
Complement C3 Deficiency Leads to Accelerated Amyloid Plaque Deposition and Neurodegeneration and Modulation of the Microglia/Macrophage Phenotype in Amyloid Precursor Protein Transgenic Mice
Maier, M., Peng, Y., Jiang, L., Seabrook, T. J., Carroll, M. C., & Lemere, C. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0829-08.2008 · Cited by 323 · see citing works
Non-Fc-Mediated Mechanisms Are Involved in Clearance of Amyloid-βIn Vivoby Immunotherapy
Bacskai, B. J., Kajdasz, S. T., McLellan, M. E., Games, D., Seubert, P., Schenk, D., & Hyman, B. T. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-18-07873.2002 · Cited by 323 · see citing works
Upregulation of TREM2 Ameliorates Neuropathology and Rescues Spatial Cognitive Impairment in a Transgenic Mouse Model of Alzheimer’s Disease
Jiang, T., Tan, L., Zhu, X.-C., Zhang, Q.-Q., Cao, L., Tan, M.-S., Gu, L.-Z., Wang, H.-F., Ding, Z.-Z., Zhang, Y.-D., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.164 · Cited by 320 · see citing works
Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation
Piccio, L. M., Buonsanti, C., Cella, M., Tassi, I., Schmidt, R. E., Fenoglio, C., Rinker, J. R., Naismith, R. T., Panina‐Bordignon, P., Passini, N., et al. (2008) · Brain · doi:10.1093/brain/awn217 · Cited by 308 · see citing works
Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism
Song, W. M., Joshita, S., Zhou, Y., Ulland, T. K., Gilfillan, S., & Colonna, M. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20171529 · Cited by 305 · see citing works
ApoE attenuates unresolvable inflammation by complex formation with activated C1q
Yin, C., Ackermann, S., Ma, Z., Mohanta, S. K., Zhang, C., Li, Y., Nietzsche, S., Westermann, M., Peng, L., Hu, D., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0336-8 · Cited by 305 · see citing works
The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E
Bailey, C. C., DeVaux, L. B., & Farzan, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677286 · Cited by 303 · see citing works
TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy
Bemiller, S. M., McCray, T. J., Allan, K., Formica, S. V., Xu, G., Wilson, G., Kokiko-Cochran, O. N., Crish, S. D., Lasagna-Reeves, C. A., Ransohoff, R. M., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0216-6 · Cited by 299 · see citing works
Alzheimer's disease‐associated TREM2 variants exhibit either decreased or increased ligand‐dependent activation
Song, W., Hooli, B., Mullin, K., Jin, S. C., Cella, M., Ulland, T. K., Wang, Y., Tanzi, R. E., & Colonna, M. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.07.004 · Cited by 297 · see citing works
ApoE facilitates the microglial response to amyloid plaque pathology
Ulrich, J. D., Ulland, T. K., Mahan, T. E., Nyström, S., Nilsson, K. P., Song, W. M., Zhou, Y., Reinartz, M., Choi, S., Jiang, H., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20171265 · Cited by 297 · see citing works
Sequential Proteolytic Processing of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Protein by Ectodomain Shedding and γ-Secretase-dependent Intramembranous Cleavage
Wunderlich, P., Glebov, K., Kemmerling, N., Tien, N. T., Neumann, H., & Walter, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.517540 · Cited by 296 · see citing works
Deciphering the Genetic Basis of Alzheimer's Disease
Selkoe, D. J., & Podlisny, M. B. (2002) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.3.022502.103022 · Cited by 293 · see citing works
Pattern Recognition by TREM-2: Binding of Anionic Ligands
Daws, M. R., Sullam, P. M., Niemi, E. C., Chen, T. T., Tchao, N. K., & Seaman, W. E. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.2.594 · Cited by 291 · see citing works
Microglia and the brain: Complementary partners in development and disease
Hammond, T. R., Robinton, D., & Stevens, B. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100616-060509 · Cited by 288 · see citing works
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TREM2-Ligand Interactions in Health and Disease
Kober, D. L., & Brett, T. J. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.04.004 · Cited by 284 · cited 4× · see citing works
“Phosphorylation of this domain leads to the recruitment of spleen tyrosine kinase (Syk), which in turn activates PI3K and Immunity 50, April 16, 2019 963 PLCg, which activate downstream signaling cascades that include ERK, AKT, NF-kB, and NFAT (Kober and Brett, 2017; McVicar et al., 1998; Mócsai et al., 2006; Mócsai…”
BackgroundInfluential
TGF-β Signaling Specifies Axons during Brain Development
Yi, J. J., Barnes, A. P., Hand, R., Polleux, F., & Ehlers, M. D. (2010) · Cell · doi:10.1016/j.cell.2010.06.010 · Cited by 284 · see citing works
Activating and inhibitory functions of DAP12
Turnbull, I. R., & Colonna, M. (2007) · Nature Reviews Immunology · doi:10.1038/nri2014 · Cited by 273 · see citing works
Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury
Suárez-Calvet, M., Araque Caballero, M. Á., Kleinberger, G., Bateman, R. J., Fagan, A. M., Morris, J. C., Levin, J., Danek, A., Ewers, M., Haass, C., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aag1767 · Cited by 272 · see citing works
Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
Guerreiro, R., Ross, O. A., Kun-Rodrigues, C., Hernandez, D. G., Orme, T., Eicher, J. D., Shepherd, C. E., Parkkinen, L., Darwent, L., Heckman, M. G., et al. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30400-3 · Cited by 270 · see citing works
Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease
Fonseca, M. I., Ager, R. R., Chu, S.-H., Yazan, O., Sanderson, S. D., LaFerla, F. M., Taylor, S. M., Woodruff, T. M., & Tenner, A. J. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901005 · Cited by 268 · see citing works
Src-family and Syk Kinases in Activating and Inhibitory Pathways in Innate Immune Cells: Signaling Cross TalkPreprint
Lowell, C. A. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a002352 · Cited by 264 · see citing works
Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer’s Disease
Fu, H., Rodriguez, G. A., Herman, M., Emrani, S., Nahmani, E., Barrett, G., Figueroa, H. Y., Goldberg, E., Hussaini, S. A., & Duff, K. E. (2017) · Neuron · doi:10.1016/j.neuron.2016.12.023 · Cited by 264 · see citing works
The Genotype-Tissue Expression (GTEx) project
Lonsdale, J., Thomas, J., Salvatore, M., Phillips, R., Lo, E., Shad, S., Hasz, R., Walters, G., Garcia, F., Young, N., et al. (2013) · Nature Genetics · doi:10.1038/ng.2653 · Cited by 263 · see citing works
The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation
Bond, A. M., Bhalala, O. G., & Kessler, J. A. (2012) · Developmental Neurobiology · doi:10.1002/dneu.22022 · Cited by 260 · see citing works
An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function
Schlepckow, K., Kleinberger, G., Fukumori, A., Feederle, R., Lichtenthaler, S. F., Steiner, H., & Haass, C. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707672 · Cited by 258 · see citing works
Impaired Differentiation of Osteoclasts in TREM-2–deficient Individuals
Cella, M., Buonsanti, C., Strader, C., Kondo, T., Salmaggi, A., & Colonna, M. (2003) · Journal of Experimental Medicine · doi:10.1084/jem.20022220 · Cited by 256 · see citing works
The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2
Klünemann, H. H., Ridha, B. H., Magy, L., Wherrett, J. R., Hemelsoet, D. M., Keen, R. W., De Bleecker, J. L., Rossor, M. N., Marienhagen, J., Klein, H. E., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000160304.00003.ca · Cited by 254 · see citing works
The Neuroprotective Functions of Transforming Growth Factor Beta Proteins
Dobolyi, Á., Vincze, C., Pál, G., & Lovas, G. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13078219 · Cited by 251 · see citing works
Genetic risk factors in Parkinson’s disease
Billingsley, K. J., Bandrés‐Ciga, S., Sáez-Atiénzar, S., & Singleton, A. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2817-y · Cited by 249 · see citing works
First‐in‐human assessment of PRX002, an anti–α‐synuclein monoclonal antibody, in healthy volunteers
Schenk, D. B., Koller, M., NESS, D. K., Griffith, S. G., Grundman, M., Zago, W. M., Soto, J., Atiee, G. J., Ostrowitzki, S., & Kinney, G. G. (2016) · Movement Disorders · doi:10.1002/mds.26878 · Cited by 248 · see citing works
Inflammation and Adaptive Immunity in Parkinson's DiseasePreprint
Mosley, R. L., Hutter-Saunders, J. A. L., Stone, D. K., & Gendelman, H. E. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009381 · Cited by 246 · see citing works
The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders
Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30232-1 · Cited by 244 · cited 4× · see citing works
“In addition, homozygous TREM2 variants were also found to be potentially casual for a form of FTD (Carmona et al., 2018; Chouery et al., 2008; Guerreiro et al., 2013a), while other variants significantly elevated FTD risk (Carmona et al.”
BackgroundInfluential
TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria
N’Diaye, E.-N., Branda, C., Branda, S. S., Nevarez, L., Colonna, M., Lowell, C. A., Hamerman, J. A., & Seaman, W. E. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200808080 · Cited by 242 · see citing works
Apolipoprotein E: Diversity of Cellular Origins, Structural and Biophysical Properties, and Effects in Alzheimer's Disease
Huang, Y., Weisgraber, K. H., Mucke, L., & Mahley, R. W. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:23:3:189 · Cited by 242 · see citing works
Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms
Kober, D. L., Alexander-Brett, J. M., Karch, C. M., Cruchaga, C., Colonna, M., Holtzman, M. J., & Brett, T. J. (2016) · eLife · doi:10.7554/elife.20391 · Cited by 238 · see citing works
Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate α-secretase activity
Kim, M., Suh, J., Romano, D., Truong, M. H., Mullin, K., Hooli, B., Norton, D., Tesco, G., Elliott, K., Wagner, S. L., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp323 · Cited by 234 · see citing works
Parkinson's disease dementia: Definitions, guidelines, and research perspectives in diagnosis
Goetz, C. G., Emre, M., & Dubois, B. (2009) · Annals of Neurology · doi:10.1002/ana.21455 · Cited by 232 · see citing works
Lewy bodies in Parkinson's disease are recognized by antibodies to complement proteins
Yamada, T., McGeer, P. L., & McGeer, E. G. (1992) · Acta Neuropathologica · doi:10.1007/bf00427222 · Cited by 231 · see citing works
Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy
Sayed, F. A., Telpoukhovskaia, M., Kodama, L., Li, Y., Zhou, Y., Le, D., Hauduc, A., Ludwig, C., Gao, F., Clelland, C., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811411115 · Cited by 229 · cited 1× · see citing works
“However, they found that haploinsufficiency, which the authors argued better mimics a partial loss of function, increased tau pathology (Sayed et al., 2018).”
Background
Localization and Cell Association of C1q in Alzheimer's Disease Brain
Afagh, A., Cummings, B. J., Cribbs, D. H., Cotman, C. W., & Tenner, A. J. (1996) · Experimental Neurology · doi:10.1006/exnr.1996.0043 · Cited by 224 · see citing works
Inflammation is genetically implicated in Parkinson’s disease
Dzamko, N., Geczy, C. L., & Halliday, G. M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2014.10.028 · Cited by 222 · see citing works
Amyloid-β Immunization Effectively Reduces Amyloid Deposition in FcRγ-/-Knock-Out Mice
Das, P., HOWARD, V. G., Loosbrock, N., Dickson, D. W., Murphy, M. P., & Golde, T. E. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-24-08532.2003 · Cited by 212 · see citing works
APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology
Dickson, D. W., Heckman, M. G., Murray, M. E., Soto, A. I., Walton, R. L., Diehl, N. N., van Gerpen, J. A., Uitti, R. J., Wszolek, Z. K., Ertekin-Taner, N., et al. (2018) · Neurology · doi:10.1212/wnl.0000000000006212 · Cited by 210 · see citing works
The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease
Lill, C. M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P. M., Wang, L., Liu, T., Lassen, C. F., Meissner, E., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.12.009 · Cited by 205 · see citing works
CNS manifestations of Nasu–Hakola disease
Bm, J., Autti, T., Raininko, R., Partanen, J., Salonen, O., Puranen, M., Hakola, P., & Haltia, M. (2001) · Neurology · doi:10.1212/wnl.56.11.1552 · Cited by 205 · see citing works
Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis
Orsini, F., Blasio, D. D., Zangari, R., Zanier, E. R., & Simoni, M. G. D. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00380 · Cited by 202 · see citing works
TREM2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant
Thornton, P., Sevalle, J., Deery, M. J., Fraser, G., Zhou, Y., Ståhl, S., Franssen, E. H., Dodd, R. B., Qamar, S., Gomez Perez‐Nievas, B., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707673 · Cited by 200 · see citing works
Convergent genetic and expression data implicate immunity in Alzheimer's disease
International Genomics of Alzheimer's Disease Consortium (IGAP), Jones, L., Lambert, J., Wang, L., Choi, S., Harold, D., Vedernikov, A., Escott‐Price, V., Stone, T., Richards, A., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.05.1757 · Cited by 199 · see citing works
Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia
Notter, T., Coughlin, J. M., Gschwind, T., Weber-Stadlbauer, U., Wang, Y.-C., Kassiou, M., Vernon, A., Benke, D., Pomper, M., Sawa, A., et al. (2018) · Molecular Psychiatry · doi:10.1038/mp.2016.248 · Cited by 195 · see citing works

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Role of neuroinflammation in neurodegeneration development
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“The pathology of AD is characterized by extracellular amyloid plaques and intracellular NFTs, which are surrounded by immune cells, especially microglia; the clinical manifestation of AD is characterized by progressive cognitive impairment.(14) The main component of the amyloid plaques is amyloid beta (Aβ), which is g…”
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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
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Authors: Hammond, T. R., Marsh, S. E., & Stevens, B.
Affiliations: Broad Institute (US)
Corresponding author: Stevens, Beth
ORCID: Hammond, Timothy R.
Marsh, Samuel E.
Stevens, Beth
Venue: Immunity
Publisher: Elsevier BV
Published: 2019-04
Volume: 50
Issue: 4
Pages: 955-974
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2019.03.016
PMC: PMC6822103
OpenAlex: W2938743978
Cited by: 336
References: 268
Citations by year: 2026: 32 · 2025: 42 · 2024: 46 · 2023: 58 · 2022: 52 · 2021: 46 · 2020: 47 · 2019: 12 · 2018: 1
FWCI: 4.06
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 381 d)
Locations: Immunity (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255, 2018, 2019)
Cure Alzheimer's Fund
National Institute on Aging (1RF1AG051496)
National Institute of Neurological Disorders and Stroke (WO2015103594A1/US20160327572A1, US8148330B2, US9149444B2)
National Institutes of Health
National Cancer Institute
National Institute on Drug Abuse
National Heart, Lung, and Blood Institute
National Institute of Mental Health
National Human Genome Research Institute
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords: neurodegeneration, immune signaling, TGF-beta, complement system, TREM2, cytokines, growth factors, genetic risk factors, genome-wide association study, neuroinflammation
MeSH terms: Aging, Animals, Complement Activation, Gliosis, Humans, Immunity, Innate, Inflammation, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Signal Transduction, Transforming Growth Factor beta, Microglia, Mice, Knockout, Models, Immunological, Disease Progression, Neurodegenerative Diseases, Genetic Predisposition to Disease, Mice, Genome-Wide Association Study, Protein Aggregation, Pathological

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