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A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease
Open accessAbstract
Neuroinflammation commences decades before Alzheimer’s disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout AD its continuum. Large-scale genome-wide association studies point out several genetic variants - TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1 - potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins cell turn-over, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs) did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof-of-mechanism may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e. TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, YKL-40. PET radio-ligands are investigated to accomplish in-vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker-drug co-development pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.
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“mitochondrial dysfunction—with reactive oxygen species (ROS) accumulation and neuroinflammation driving microglial activation—plays a central role in AD pathogenesis [56]”
From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [56]
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“Preliminary evidence from experimental studies suggests that the phenotypic transformation of the activated M1/M2 functional states (“phenotypic switching”) (48, 49) can be determined by both the stage and the severity of the disease.”
BackgroundProtective effects of NSAIDs on the development of Alzheimer disease
Vlad, S. C., Miller, D. R., Kowall, N. W., & Felson, D. T. (2008) · Neurology · doi:10.1212/01.wnl.0000311269.57716.63 · Cited by 535
Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance
Bolmont, T., Haiss, F., Eicke, D., Radde, R., Mathis, C. A., Klunk, W. E., Kohsaka, S., Jucker, M., & Calhoun, M. E. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4814-07.2008 · Cited by 526 · cited 1×
“Microglia eliminate Aβ peptides and dying/dead cells through phagocytosis (59, 60).”
BackgroundMicroglia during development and aging
Harry, G. J. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.04.013 · Cited by 524 · cited 1×
“Indeed, an age-related ultrastructural and functional shift of microglia cells is associated with increased synaptic susceptibility and neurodegeneration (35).”
BackgroundCurrent 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 · cited 2×
“Even though the A/T/N classification scheme provides crucial pathophysiological insights, it offers a partial depiction of the spectrum of pathomechanistic modifications of AD (10, 11).”
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Etminan, M., Gill, S., & Samii, A. (2003) · BMJ · doi:10.1136/bmj.327.7407.128 · Cited by 511
A Cell Surface Receptor Complex for Fibrillar β-Amyloid Mediates Microglial Activation
Bamberger, M. E., Harris, M. E., McDonald, D. R., Husemann, J., & Landreth, G. E. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-07-02665.2003 · Cited by 501
Olabarria, M., Noristani, H. N., Verkhratsky, A., & Rodríguez, J. J. (2010) · Glia · doi:10.1002/glia.20967 · Cited by 499 · cited 1×
“Along with microglia activation, hypertrophic reactive astrocytes gather around Aβ plaques as reported in human postmortem studies (82) as well as in animal models (83).”
BackgroundNSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies
McGeer, P. L., & McGeer, E. G. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.03.013 · Cited by 498 · cited 1×
“Investigations conducted in transgenic AD mice also address the effects of NSAIDs on amyloid load and inflammation (152).”
BackgroundPhysical Activity and Hemostatic and Inflammatory Variables in Elderly Men
Wannamethee, S. G., Lowe, G. D. O., Whincup, P. H., Rumley, A., Walker, M., & Lennon, L. (2002) · Circulation · doi:10.1161/01.cir.0000016346.14762.71 · Cited by 487
Koenigsknecht-Talboo, J., & Landreth, G. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1808-05.2005 · Cited by 477
A randomized controlled trial of prednisone in Alzheimer’s disease
Aisen, P. S., Davis, K. L., Berg, J. D., Schafer, K., Campbell, K., Thomas, R. G., Weiner, M. F., Farlow, M. R., Sano, M., Grundman, M., et al. (2000) · Neurology · doi:10.1212/wnl.54.3.588 · Cited by 464
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“Neuroinflammation can be measured more specifically using targeted radio-ligands for PET imaging— that allow accomplishing the regional in vivo exploration of neuroinflammation—like [11C]-PK11195 (185).”
BackgroundInflammation, microglia, and alzheimer's disease
Cameron, B., & Landreth, G. E. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.10.006 · Cited by 452
Brosseron, F., Krauthausen, M., Kummer, M., & Heneka, M. T. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8657-1 · Cited by 447 · cited 4×
“Notably, the TNF-α receptor complex and its functional proteins are assumed to play a crucial role since they link neuroinflammatory pathways to amyloid deposition process in a chronically damaging and selfperpetuating way (21).”
BackgroundInfluentialProminent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice
Wyss-Coray, T., Yan, F., Lin, A. H.-T., Lambris, J. D., Alexander, J. J., Quigg, R. J., & Masliah, E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.162350199 · Cited by 446 · cited 1×
“There is a growing interest on the role of complement and microglia in AD pathology (147).”
BackgroundInflammation and Alzheimer's disease pathogenesis
Rogers, J., Webster, S. D., Lue, L., Brachova, L., CIVIN, W. H., Emmerling, M. R., Shivers, B. D., Walker, D. G., & McGeer, P. L. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00115-7 · Cited by 438
An early and late peak in microglial activation in Alzheimer’s disease trajectory
Fan, Z., Brooks, D. J., Okello, A., & Edison, P. (2017) · Brain · doi:10.1093/brain/aww349 · Cited by 438
Lai, K. S. P., Liu, C. S., Rau, A., Lanctôt, K. L., Köhler, C. A., Pakosh, M., Carvalho, A. F., & Herrmann, N. (2017) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-316201 · Cited by 433 · cited 7×
“A recent meta-analysis reports higher concentration of YKL-40, sTREM2, MCP-1, and TGF-β in the CSF of AD patients compared to controls (160).”
BackgroundMethodInfluentialLourenco, M. V., Clarke, J. R., Frozza, R. L., Bomfim, T. R., Forny‐Germano, L., Batista, A. F., Sathler, L. B., Brito‐Moreira, J., Amaral, O. B., Silva, C. A., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.11.002 · Cited by 430 · cited 1×
“Finally, TNF-α significantly contributes to promote insulin resistance and the following cognitive decline in AD (118, 119).”
BackgroundInhibition of IL-12/IL-23 signaling reduces Alzheimer's disease–like pathology and cognitive decline
vom Berg, J., Prokop, S., Miller, K. R., Obst, J., Kälin, R. E., Lopategui-Cabezas, I., Wegner, A., Mair, F., Schipke, C. G., Peters, O., et al. (2012) · Nature Medicine · doi:10.1038/nm.2965 · Cited by 416 · cited 15×
“Actually, a trial recruiting MCI individuals highlights that rofecoxib could rush the conversion to AD (223).”
BackgroundInfluentialNonsteroidal Anti-Inflammatory Drugs for the Prevention of Alzheimer’s Disease: A Systematic Review
Szekely, C. A., Thorne, J. E., Zandi, P. P., Ek, M., Messias, E., Breitner, J. C. S., & Goodman, S. N. (2004) · Neuroepidemiology · doi:10.1159/000078501 · Cited by 402
A Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment
on behalf of the Rofecoxib Protocol 078 study group, Thal, L. J., Ferris, S. H., Kirby, L., Block, G. A., Lines, C. R., Yuen, E., Assaid, C., Nessly, M. L., Norman, B. A., et al. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300690 · Cited by 402
The origin and cell lineage of microglia: new concepts
Chan, W. Y., Kohsaka, S., & Rezaie, P. (2007) · Brain Research Reviews · doi:10.1016/j.brainresrev.2006.11.002 · Cited by 400 · cited 1×
“The Role of Microglia Microglial cells, arising from the mesodermal (myeloid) lineage (42), are the main category of macrophages in the CNS parenchyma.”
BackgroundLiao, Y.-F., Wang, B.-J., Cheng, H.-T., Kuo, L.-H., & Wolfe, M. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402034200 · Cited by 389 · cited 1×
“On the other hand, TNF-α can stimulate γ-secretase activity, which results in an increased synthesis of Aβ peptides and a further increase in TNF-α release (113, 116).”
BackgroundShen, X.-N., Niu, L.-D., Wang, Y.-J., Cao, X.-P., Liu, Q., Tan, L., Zhang, C., & Yu, J.-T. (2019) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2018-319148 · Cited by 388 · cited 2×
“A recent meta-analysis reports higher concentration of YKL-40, sTREM2, MCP-1, and TGF-β in the CSF of AD patients compared to controls (160).”
BackgroundA double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease
Scharf, S., Mander, A. G., Ugoni, A., Vajda, F. J. E., & Christophidis, N. (1999) · Neurology · doi:10.1212/wnl.53.1.197 · Cited by 385
Reines, S. A., Block, G. A., Morris, J. C., Liu, G., Nessly, M. L., Lines, C. R., Norman, B., & Baranak, C. C. (2004) · Neurology · doi:10.1212/wnl.62.1.66 · Cited by 384
Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease
Decourt, B., Lahiri, D. K., & Sabbagh, M. N. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160930110551 · Cited by 383 · cited 5×
“However, both TNF-α and TNF-RI concentrations are increased in postmortem brains of early-stage AD patients (113).”
BackgroundInfluentialMicroglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity
Palazuelos, J., Aguado, T., Pazos, M. R., Julien, B., Carrasco, C., Resel, E., Sagredo, O., Benito, C., Romero, J., Azcoitia, I., et al. (2009) · Brain · doi:10.1093/brain/awp239 · Cited by 382 · cited 1×
“In addition, the cannabinoid receptor type 2 (CB2R) is subject to upregulation in activated microglia in various ND (202), possibly in conjunction with a neuroprotective effect (203), and postmortem studies emphasize the potential of compounds like [11C]-RS-016, which show high specific binding (204).”
BackgroundA randomized controlled trial of prednisone in Alzheimer’s disease
Koch, H. J., & Szecsey, A. (2000) · Neurology · doi:10.1212/wnl.55.7.1067 · Cited by 381
Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography Imaging
Lavisse, S., Guillermier, M., Hérard, A., Petit, F., Delahaye, M., Camp, N. V., Haim, L. B., Lebon, V., Rémy, P., Dollé, F., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1487-12.2012 · Cited by 381 · cited 1×
“However, one should also note that translocator protein (TSPO) gene polymorphisms can greatly affect binding affinity (192), and TSPO expression is not circumscribed to activated microglia, which can also occur on astrocytes, or endothelial cells (193).”
BackgroundTREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease
Griciuc, A., Patel, S., Federico, A. N., Choi, S. H., Innes, B. J., Oram, M. K., Cereghetti, G., McGinty, D., Anselmo, A., Sadreyev, R. I., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.06.010 · Cited by 378 · cited 1×
“Finally, Tanzi and colleagues, after exploring the potential role of the cross-talk between CD33 and TREM2 in both neuroinflammation and the cause of AD, propose that TREM2 is working downstream of CD33 to modulate the neuroinflammatory process (99).”
BackgroundSoluble 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 372 · cited 1×
“, stimulates the production of inflammatory cytokines) in response to Aβ plaques and tau tangles (94, 95).”
BackgroundHe, X.-F., Liu, D.-X., Zhang, Q., Liang, F.-Y., Dai, G.-Y., Zeng, J.-S., Pei, Z., Xu, G.-Q., & Lan, Y. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00144 · Cited by 371
Bisht, K., Sharma, K. P., & Tremblay, M. (2018) · Neurobiology of Stress · doi:10.1016/j.ynstr.2018.05.003 · Cited by 366 · cited 1×
“Proinflammatory microglial activities may be detrimental in AD due to reactive oxygen and nitrogen intermediate species—ROS and RNS, respectively—leading to oxidative stress-induced neuronal death, which could be further exacerbated by chronic stress (109, 110).”
BackgroundMixed-Affinity Binding in Humans with 18-kDa Translocator Protein Ligands
Owen, D. R., Gunn, R. N., Rabiner, E. A., Bennacef, I., Fujita, M., Kreisl, W. C., Innis, R. B., Pike, V. W., Reynolds, R., Matthews, P. M., et al. (2010) · Journal of Nuclear Medicine · doi:10.2967/jnumed.110.079459 · Cited by 361 · cited 2×
“In addition, a very recent tracer named [18F]-FEPPA is able to provide a high potential for TSPO-PET in humans (192).”
BackgroundDeficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology
Tesseur, I., Zou, K., Esposito, L., Bard, F., Berber, E., Can, J. V., Lin, A. H., Crews, L., Tremblay, P., Mathews, P., et al. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27341 · Cited by 355 · cited 1×
“A selective impairment of TGF-β1 pathway is present in early AD, both in the AD brain (121, 122) and in AD animal models (71, 123, 124).”
BackgroundMicroglia-Mediated Synapse Loss in Alzheimer's Disease
Rajendran, L., & Paolicelli, R. C. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.1136-17.2017 · Cited by 355
Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial
ADAPT Research Group (2007) · Neurology · doi:10.1212/01.wnl.0000260269.93245.d2 · Cited by 354
Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J. A., Funk, C. C., Moore, B., DiNunno, N., Rosario, A. M., Cruz, P. E., Verbeeck, C., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.11.020 · Cited by 354 · cited 1×
“On the other hand, IL-10 seems to play a protective role since delivery of this cytokine via adeno-associated virus leads to markedly decreased microgliosis and astrogliosis as well as reversed cognitive impairment in transgenic AD mice (145), although the use of a different adeno-associated virus approach generates a…”
MethodInterleukin-1, neuroinflammation, and Alzheimer's disease
Mrak, R. E. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00287-1 · Cited by 353 · cited 1×
“Similarly to TNF-α, also the proinflammatory cytokine IL-1β mediates the synaptotoxic effects of Aβ peptide (140).”
BackgroundReactive oxygen and nitrogen species as intracellular signals in skeletal muscle
Powers, S. K., Talbert, E. E., & Adhihetty, P. J. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2010.201327 · Cited by 349
LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide
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Exercise, inflammation and aging.
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The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications
Arranz, A. M., & De Strooper, B. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30490-3 · Cited by 334
Streit, W. J., Xue, Q.-S., Tischer, J., & Bechmann, I. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0142-6 · Cited by 317 · cited 3×
“Experimental models of AD demonstrate that microglia cluster around plaques, likely via chemotactic mechanisms, and may contribute both in Aβ (39, 44) clearance and in limiting the growth and further accumulation plaques (39, 44).”
BackgroundCannabinoid CB 2 receptors in human brain inflammation
Benito, C., Tolón, R. M., Pazos, M. R., Núñez, E., Castillo, A. I., & Romero, J. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707505 · Cited by 304
Logovinsky, V., Satlin, A., Lai, R. Y. K., Swanson, C. J., Kaplow, J. M., Osswald, G., Basun, H., & Lannfelt, L. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0181-2 · Cited by 302
Tau PET imaging: present and future directions
Saint‐Aubert, L., Lemoine, L., Chiotis, K., Leuzy, A., Rodriguez‐Vieitez, E., & Nordberg, A. K. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0162-3 · Cited by 300 · cited 1×
“In addition, hyperphosphorylation and abnormal aggregation of tau, which is crucial to neuronal activity, can be imaged using definite tracers, using specific ligands: T807, Flortaucipir as well as the phenyl/pyridinyl-butadienyl-benzothiazole/benzothiazolium derivative PBB3 (197, 198).”
BackgroundPhysical Activity and Hemostatic and Inflammatory Variables in Elderly Men
Wannamethee, S. G. (2002) · Circulation · doi:10.1161/hc1502.107117 · Cited by 296
Sensitive ELISA detection of amyloid‐β protofibrils in biological samples
Englund, H., Sehlin, D., Johansson, A., Nilsson, L. N. G., Gellerfors, P., Paulie, S., Lannfelt, L., & Pettersson, F. E. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04759.x · Cited by 292
Inflammatory mechanisms in Alzheimer's disease
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“In addition, rodent models of AD indicate the ability of astrocytes to uptake and clear Aβ in subjects bearing cerebral fibrillar aggregates and diffuse plaques (16, 17, 33, 86).”
BackgroundWilcock, G. K., Black, S. E., Hendrix, S. B., Zavitz, K. H., Swabb, E. A., & Laughlin, M. A. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70090-5 · Cited by 291
Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles
Joshi, P., Turola, E., Ruiz, A., Bergami, A., Libera, D. D., Benussi, L., Giussani, P., Magnani, G., Comı, G., Legname, G., et al. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.180 · Cited by 289 · cited 1×
“Extracellular vesicles—constituted by microvesicles and exosomes and released by reactive microglia—play a role in AD pathogenesis (64) (Figure 1).”
BackgroundAstrocyte senescence: Evidence and significance
Cohen, J., & Torres, C. (2019) · Aging Cell · doi:10.1111/acel.12937 · Cited by 281
Endocrine Crosstalk Between Skeletal Muscle and the Brain
Delezie, J., & Handschin, C. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00698 · Cited by 277
McAlpine, F. E., Lee, J., Harms, A. S., Ruhn, K. A., Blurton-Jones, M. M., Hong, J. J., Das, P., Golde, T. E., LaFerla, F. M., Oddo, S., et al. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.01.006 · Cited by 274
Glial activation and inflammation along the Alzheimer’s disease continuum
Nordengen, K., Kirsebom, B.-E., Henjum, K., Selnes, P., Gísladóttir, B., Wettergreen, M., Torsetnes, S. B., Grøntvedt, G. R., Waterloo, K. K., Aarsland, D., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1399-2 · Cited by 274
Cytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism
Chao, C. C., Hu, S., Sheng, W. S., Bu, D.-F., Bukrinsky, M., & Peterson, P. K. (1996) · Glia · doi:10.1002/(sici)1098-1136(199603)16:3 · Cited by 273
Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease
Villegas-Llerena, C., Phillips, A., Garcia-Reitboeck, P., Hardy, J., & Pocock, J. M. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2015.10.004 · Cited by 270 · cited 1×
“PET Radiotracers Targeting Neuroinflammation in Alzheimer’s Disease: State-of-the-Art on Human Studies There are several genetic association studies highlighting a key role of neuroinflammation in AD by demonstrating the occurrence of specific genetic variations related to immune response in patients with ND including…”
BackgroundAmyloid β-Protein Dimers Rapidly Form Stable Synaptotoxic Protofibrils
O'Nuallain, B., Freir, D. B., Nicoll, A. J., Risse, E., Ferguson, N., Herron, C. E., Collinge, J., & Walsh, D. M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3537-10.2010 · Cited by 259
Morris, E., Chalkidou, A., Hammers, A., Peacock, J. L., Summers, J. A., & Keevil, S. (2015) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-015-3228-x · Cited by 258
Inactivation of TNF Signaling by Rationally Designed Dominant-Negative TNF Variants
Steed, P. M., Tansey, M. G., Zalevsky, J., Zhukovsky, E. A., Desjarlais, J. R., Szymkowski, D. E., Abbott, C. M., Carmichael, D. F., Chan, C. S. C., Cherry, L., et al. (2003) · Science · doi:10.1126/science.1081297 · Cited by 256
Astrocytes: Conductors of the Alzheimer disease neuroinflammatory symphony
Medeiros, R., & LaFerla, F. M. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.10.007 · Cited by 248 · cited 1×
“Along with microglia activation, hypertrophic reactive astrocytes gather around Aβ plaques as reported in human postmortem studies (82) as well as in animal models (83).”
BackgroundOosterhof, N., Chang, I. J., Karimiani, E. G., Kuil, L. E., Jensen, D. M., Daza, R., Young, E., Astle, L., van der Linde, H. C., Shivaram, G. M., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.03.010 · Cited by 247 · cited 1×
“The consequences are the presence of abnormalities not only in brain structures, like corpus callosum, but also in bones that, in some cases, are overly dense and malformed (103, 104).”
BackgroundDuffy, D., Rouilly, V., Libri, V., Hasan, M., Beitz, B., David, M., Urrutia, A., Bisiaux, A., LaBrie, S. T., Dubois, A., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.03.002 · Cited by 242
Brain-Derived Neurotrophic Factor in Alzheimer’s Disease: Risk, Mechanisms, and Therapy
Song, J., Yu, J., & Tan, L. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8958-4 · Cited by 239
Intersection of population variation and autoimmunity genetics in human T cell activation
Ye, C. J., Feng, T., Kwon, H.-K., Raj, T., Wilson, M. T., Asinovski, N., McCabe, C., Lee, M. H., Frohlich, I., Paik, H.-I., et al. (2014) · Science · doi:10.1126/science.1254665 · Cited by 236
Absence of CX3CR1 impairs the internalization of Tau by microglia
Bolós, M., Llorens-Martín, M., Perea, J. R., Jurado-Arjona, J., Rábano, A., Hernández, F., & Avila, J. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0200-1 · Cited by 231 · cited 1×
“In this scenario, microglial CX3CR1 acts like a receptor for extracellular tau, since the absence of CX3CR1 impairs the internalization of tau microglia (100).”
BackgroundSelf-citationA Serum Protein–Based Algorithm for the Detection of Alzheimer Disease
O’Bryant, S. E. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.215 · Cited by 230
Kiyota, T., Dixie, K. L. I., Swan, R. J., Jacobsen, M. T., Andrews, S. J., & Ikezu, T. (2011) · Gene Therapy · doi:10.1038/gt.2011.126 · Cited by 230 · cited 1×
“On the other hand, IL-10 seems to play a protective role since delivery of this cytokine via adeno-associated virus leads to markedly decreased microgliosis and astrogliosis as well as reversed cognitive impairment in transgenic AD mice (145), although the use of a different adeno-associated virus approach generates a…”
MethodTebani, A., Afonso, C., Marret, S., & Bekri, S. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17091555 · Cited by 228
Kotilinek, L., Westerman, M. A., Wang, Q., Panizzon, K. L., Lim, G. P., Simonyi, Á., Lesné, S., Falinska, A. M., Younkin, L. H., Younkin, S. G., et al. (2008) · Brain · doi:10.1093/brain/awn008 · Cited by 223 · cited 1×
“Of note, two selective cyclooxygenase-2 (COX-2) inhibitors are found to be effective in rescuing LTP impairment by synthetic soluble Aβ1−42, whereas the same effect is not achieved with the cyclooxygenase-1 (COX-1) inhibitor piroxicam (154).”
BackgroundInterleukin-1β impairs brain derived neurotrophic factor-induced signal transduction
Tong, L., Balazs, R., Soiampornkul, R., Thangnipon, W., & Cotman, C. W. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.02.027 · Cited by 222
Lu, Y., Dong, Y., Tucker, D., Wang, R., Ahmed, M. E., Brann, D. W., & Zhang, Q. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-160869 · Cited by 222
TREM2 and the neuroimmunology of Alzheimer's disease
Hickman, S. E., & El Khoury, J. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.11.021 · Cited by 221 · cited 1×
“TREM2 variants cause AD by decreasing the Aβ phagocytic ability of microglia and through the dysregulation of the proinflammatory response of these immune cells (96).”
BackgroundPhagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease
Gomez‐Arboledas, A., Davila, J. C., Sanchez‐Mejias, E., Navarro, V., Nuñez‐Diaz, C., Sanchez‐Varo, R., Sanchez‐Mico, M. V., Trujillo‐Estrada, L., Fernandez‐Valenzuela, J. J., Vizuete, M., et al. (2018) · Glia · doi:10.1002/glia.23270 · Cited by 220 · cited 2×
“In addition, rodent models of AD indicate the ability of astrocytes to uptake and clear Aβ in subjects bearing cerebral fibrillar aggregates and diffuse plaques (16, 17, 33, 86).”
BackgroundCerebral pattern of pro- and anti-inflammatory cytokines in dementias
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“Some evidence suggest that IL-1β is produced and secreted by microglia cells in response to Aβ deposition, thus resulting in chronic neuroinflammation and, eventually, neuronal disruption, dysfunction, and neurodegeneration (173, 174).”
BackgroundImmune Players in the CNS: The Astrocyte
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“The Role of Astrocytes Astrocytes, differently from microglia and similarly to neurons and oligodendrocytes, arise from the neuroectoderm (74).”
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“Most of the failed AD clinical trials—including trials investigating anti-inflammatory compounds—did not assess any biological in vivo identification of AD-related pathomechanistic alterations, thus preventing proof of mechanisms (157) and including a percentage of subject displaying non-AD pathophysiology (158).”
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“A number of studies show alterations in [11C]-PK11195 binding in AD and several other ND (186–189), Parkinson’s disease (190), and progressive supranuclear palsy (189, 191), and the distributions of [11C]-PK11195 found in these studies are akin to the wellknown distribution of neurodegeneration (e.”
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18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy
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Alzheimer’s Disease, Oligomers, and Inflammation
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“Like microglia, astrocytes are also activated by tissue injury, infection, and inflammation (84).”
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Randomized pilot study of nimesulide treatment in Alzheimer’s disease
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“Indeed, the clinical picture of MCI is heterogeneous not only with a 10–15% annual rate of developing AD (178) but also with a consistent proportion of individuals who recover, remain stable, or develop ND other than AD (179).”
BackgroundMicroglial activation in Alzheimer's disease: an (R)-[11C]PK11195 positron emission tomography study
Schuitemaker, A., Kropholler, M. A., Boellaard, R., van der Flier, W. M., Kloet, R. W., van der Doef, T. F., Knol, D. L., Windhorst, A. D., Luurtsema, G., Barkhof, F., et al. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.04.021 · Cited by 175
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Caraci, F., Spampinato, S. F., Morgese, M. G., Tascedda, F., Salluzzo, M. G., Giambirtone, M. C., Caruso, G., Munafò, A., Torrisi, S. A., Leggio, G. M., et al. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.02.007 · Cited by 172 · cited 3×
“Such an atypical stimulation of cerebral innate immunity is responsible for reduced serotonergic tonus, a primary event in depression due to Aβ, a prodromal symptom of AD (70).”
BackgroundInfluentialSelf-citationEarly and Late CNS Inflammation in Alzheimer’s Disease: Two Extremes of a Continuum?
Cuello, A. C. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.07.005 · Cited by 170 · cited 2×
“CNS inflammation as an encouraging target to prevent the advancement of the pathology (19).”
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Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease
Hanzel, C. E., Binette, A. P., Pimentel, L. S. B., Iulita, M. F., Allard, S. T. M., Ducatenzeiler, A., Carmo, S. D., & Cuello, A. C. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.03.026 · Cited by 164 · cited 1×
“This early proinflammatory process is characterized by neuronal and microglia-derived cytokines and chemokines as well as by mobilization of microglia toward Aβ-burdened neurons (Figure 2) (19, 72).”
BackgroundSelf-citationIncreased Matrix Metalloproteinase 9 Activity in Mild Cognitive Impairment
Bruno, M. A., Mufson, E. J., Wuu, J., & Cuello, A. C. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181c22569 · Cited by 163 · cited 1×
“Neuroinflammatory processes promote an overactivation of metalloprotease-9 (MMP-9), as observed in the brains of Down syndrome patients (132), MCI subjects, and AD patients (135).”
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“Finally, there are other molecular targets that can offer a more exhaustive depiction of in vivo neuroinflammation (200).”
BackgroundInflammatory Proteins in Plasma Are Associated with Severity of Alzheimer’s Disease
Leung, R., Proitsi, P., Simmons, A., Lunnon, K., Güntert, A., Kronenberg, D., Pritchard, M., Tsolaki, M., Mecocci, P., Kloszewska, I., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064971 · Cited by 160
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Exercise reduces activation of microglia isolated from hippocampus and brain of aged mice
Kohman, R. A., Bhattacharya, T. K., Wojcik, E., & Rhodes, J. S. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-114 · Cited by 155
Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration
Henstridge, C. M., Tzioras, M., & Paolicelli, R. C. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00063 · Cited by 155 · cited 1×
“In general, these cells play a substantial role in neural transmission and synapse remodeling, as they facilitate the removal of nonessential synapses by eradicating inadequate connections (27, 28).”
BackgroundAmyloid β-Induced Nerve Growth Factor Dysmetabolism in Alzheimer Disease
Bruno, M. A., León, W., Fragoso, G., Mushynski, W. E., Almazán, G., & Cuello, A. C. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181aed9e6 · Cited by 152 · cited 1×
“Studies in transgenic animal models of AD indicate that the proinflammatory process—initiated before plaque deposition and promoted by soluble Aβ oligomers—leads to an impairment of NGF metabolic pathway characterized by a reduced conversion of the precursor proNGF to the mature NGF (mNGF) as well as by an increased d…”
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“TGFβ1 displays both anti-inflammatory and neuroprotective actions (123, 125) and stimulates Aβ clearance by microglia (126).”
Backgroundde Jong, D., Jansen, R. W. M. M., Hoefnagels, W. H. L., Mj, J.-E., Verbeek, M. M., Borm, G. F., & Kremer, B. P. H. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001475 · Cited by 150
Peripheral Inflammatory Cytokines as Biomarkers in Alzheimer’s Disease and Mild Cognitive Impairment
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“Actually, a trial recruiting MCI individuals highlights that rofecoxib could rush the conversion to AD (223).”
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“Today, it is widely accepted that oxidative stress is strongly associated with the inflammation observed in AD (108).”
BackgroundInterleukin‐6 and acute coronary syndrome
Ikeda, U., Ito, T., & Shimada, K. (2001) · Clinical Cardiology · doi:10.1002/clc.4960241103 · Cited by 147 · cited 1×
“For instance, persistent higher plasma levels of IL-1β and IL-6 are observed in relation to cardiovascular diseases as well as atherosclerosis (181, 182).”
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Long-Term Efficacy and Safety of Celecoxib in Alzheimer’s Disease
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Bhaskar, K., Maphis, N. M., Xu, G., Varvel, N. H., Kokiko‐Cochran, O. N., Weick, J. P., Staugaitis, S. M., Cardona, A. E., Ransohoff, R. M., Herrup, K., et al. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.10.007 · Cited by 141 · cited 4×
“Neuroinflammatory pathways and microglial cells activation are associated with neuronal ectopic cell cycle activation (105).”
BackgroundInfluentialA unifying hypothesis for Alzheimer's disease: from plaques to neurodegeneration
Edwards, F. A. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.03.003 · Cited by 140 · cited 2×
“Experimental models of AD demonstrate that microglia cluster around plaques, likely via chemotactic mechanisms, and may contribute both in Aβ (39, 44) clearance and in limiting the growth and further accumulation plaques (39, 44).”
BackgroundCytokine Response to Exercise and Its Modulation
Suzuki, K. (2018) · Antioxidants · doi:10.3390/antiox7010017 · Cited by 139
Ledo, J. H., Azevedo, E. P., Beckman, D., Ribeiro, F. C., Santos, L. E., Razolli, D. S., Kincheski, G. C., Melo, H. M., Bellio, M., Teixeira, A. L., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1269-16.2016 · Cited by 138
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β‐amyloid inhibition of long‐term potentiation is mediated via tumor necrosis factor
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“Accordingly, mutant mice lacking TNF receptor type 1 exhibit normal LTP following Aβ application and similar results are obtained with the use of anti-TNF agents including the monoclonal antibody infliximab and thalidomide, which also inhibits TNFα production (138).”
ResultA key role for TGF-β1 in hippocampal synaptic plasticity and memory
Caraci, F., Gulisano, W., Guida, C. A., Impellizzeri, A. A. R., Drago, F., Puzzo, D., & Palmeri, A. (2015) · Scientific Reports · doi:10.1038/srep11252 · Cited by 133 · cited 7×
“Of note, two selective cyclooxygenase-2 (COX-2) inhibitors are found to be effective in rescuing LTP impairment by synthetic soluble Aβ1−42, whereas the same effect is not achieved with the cyclooxygenase-1 (COX-1) inhibitor piroxicam (154).”
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Targeting TNF: a therapeutic strategy for Alzheimer's disease
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“Among the different mediators of inflammation explored, TNFα mediates proinflammatory processes in various ND including AD (136).”
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Self-citationInferring relevant cell types for complex traits by using single-cell gene expression
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Meta-Analysis of Nonsteroidal Antiinflammatory Drug Use and Risk of Dementia
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Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer’s disease
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Effect of Exercise on Inflammatory Profile of Older Persons: Systematic Review and Meta-Analyses
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- Presented at the 11thClinical Trials on Alzheimer's Disease (CTAD) Conference October 24–272018
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Economic burden of Alzheimer disease and managed care considerations
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The Role of NLRP3 Inflammasome in Alzheimer’s Disease and Potential Therapeutic Targets
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Role of Inflammatory Processes in Hemorrhagic Stroke
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The role of innate immune genes in Alzheimer's disease
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“Neuroinflammation is as an innate immunological response of the central nervous system that is characterized by the activation of microglia and astrocytes, which play a central role in Alzheimer’s disease pathogenesis [24].”
Background
Metadata
- Authors
- Hampel, H., Caraci, F., Cuello, A. C., Caruso, G., Nisticò, R., Corbo, M., Baldacci, F., Toschi, N., Garaci, F., Chiesa, P. A., Verdooner, S. R., Akman-Anderson, L., Hernández, F., Ávila, J., Emanuele, E., Valenzuela, P. L., Lucía, A., Watling, M., Imbimbo, B. P., Vergallo, A., & Lista, S.
- Affiliations
- Sorbonne Université (FR)
- University of Catania (IT)
- University of Oxford (GB)
- I.R.C.C.S. Oasi Maria SS (IT)
- University of Rome Tor Vergata (IT)
- University of Pisa (IT)
- Centre National de la Recherche Scientifique (FR)
- Consejo Superior de Investigaciones Científicas (ES)
- Universidad de Alcalá (ES)
- Research Institute Hospital 12 de Octubre (ES)
- Chiesi (Italy) (IT)
- Corresponding author
- Hampel, Harald
- ORCID
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2020-03-31
- Volume
- 11
- Pages
- 456-456
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC7137904
- OpenAlex
- W3014540555
- Cited by
- 360
- References
- 297
- Citations by year
- 2026: 43 · 2025: 53 · 2024: 53 · 2023: 66 · 2022: 69 · 2021: 49 · 2020: 22
- FWCI
- 5.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, cc-by)
- Biblos-e Archivo (Universidad Autónoma de Madrid) (submittedVersion, cc-by)
- ABACUS. Repositorio de Producción Científica (Universidad Europea) (submittedVersion, cc-by-nc-nd)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, other-oa)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hispana (submittedVersion)
- Funders
- AXA Research Fund
- Eisai
- Sorbonne Université
- Fondation pour la Recherche sur Alzheimer
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, neuroinflammation, TREM2, microglia, astrocytes, amyloid-beta, tau protein, synaptotoxicity, neurodegeneration, genetic risk variants, cytokines, TNF-α, IL-1β, TGF-beta, biomarkers, positron emission tomography, nonsteroidal anti-inflammatory drugs, disease-modifying therapy, precision medicine
- MeSH terms
- Cell Self Renewal, Alzheimer Disease, Animals, Humans, Signal Transduction, Cytokines, Neurogenic Inflammation, Proteomics, Systems Biology, Lipid Metabolism, Genome-Wide Association Study, Precision Medicine
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