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 ROS accumulation and neuroinflammation driving microglial activation-plays a central role in AD pathogenesis.
“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]
The ‘Cellular and Molecular Neuroinflammatory Pathways’ section links oxidative stress, neuroinflammation, microglia and ROS in AD; the ‘Role of Microglia’ section also describes harmful microglial activation. But the paper does not identify mitochondrial dysfunction as central to this pathway, and it describes activated microglia producing ROS rather than ROS driving their activation. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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Initiative, T. A. D. N., Bradshaw, E. M., Chibnik, L. B., Keenan, B. T., Ottoboni, L., Raj, T., Tang, A., Rosenkrantz, L. L., Imboywa, S., Lee, M., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3435 · Cited by 570 · see citing works
The “quad‐partite” synapse: Microglia‐synapse interactions in the developing and mature CNS
Schafer, D. P., Lehrman, E. K., & Stevens, B. (2013) · Glia · doi:10.1002/glia.22389 · Cited by 570 · cited 1× · see citing works
“The Role of Microglia and Astrocytes in Alzheimer’s Disease Synaptic Dysfunction Synapses exhibit a quad-partite arrangement that consists of an axon terminal, a dendritic spine put in direct communication with a microglial and an astrocytic process (29).”
BackgroundMicroglial subtypes: diversity within the microglial community
Stratoulias, V., Venero, J. L., Tremblay, M., & Joseph, B. (2019) · The EMBO Journal · doi:10.15252/embj.2019101997 · Cited by 536 · cited 1× · see citing works
“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 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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 · see citing works
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 · see citing works
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“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× · see citing works
“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 · see citing works
Koenigsknecht-Talboo, J., & Landreth, G. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1808-05.2005 · Cited by 477 · see citing works
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 · see citing works
Cosenza‐Nashat, M., Zhao, M. ‐., Suh, H. ‐., Morgan, J., Natividad, R., Morgello, S., & Lee, S. C. (2009) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2008.01006.x · Cited by 459 · cited 1× · see citing works
“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).”
BackgroundBrosseron, F., Krauthausen, M., Kummer, M., & Heneka, M. T. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8657-1 · Cited by 447 · cited 4× · see citing works
“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× · see citing works
“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 441 · see citing works
Inflammation, microglia, and alzheimer's disease
Cameron, B., & Landreth, G. E. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.10.006 · Cited by 440 · see citing works
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× · see citing works
“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).”
BackgroundMethodInfluentialAn 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 422 · see citing works
Inhibition 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× · see citing works
“Actually, a trial recruiting MCI individuals highlights that rofecoxib could rush the conversion to AD (223).”
BackgroundInfluentialLourenco, 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 415 · cited 1× · see citing works
“Finally, TNF-α significantly contributes to promote insulin resistance and the following cognitive decline in AD (118, 119).”
BackgroundA 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 · see citing works
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× · see citing works
“The Role of Microglia Microglial cells, arising from the mesodermal (myeloid) lineage (42), are the main category of macrophages in the CNS parenchyma.”
BackgroundNonsteroidal 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 394 · see citing works
Liao, 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× · see citing works
“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× · see citing works
“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 · see citing works
Microglial 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× · see citing works
“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 · see citing works
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 378 · see citing works
TREM2 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× · see citing works
“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).”
BackgroundTargeting 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 373 · cited 5× · see citing works
“However, both TNF-α and TNF-RI concentrations are increased in postmortem brains of early-stage AD patients (113).”
BackgroundInfluentialHe, 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 · see citing works
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 362 · cited 1× · see citing works
“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).”
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× · see citing works
“In addition, a very recent tracer named [18F]-FEPPA is able to provide a high potential for TSPO-PET in humans (192).”
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 358 · cited 1× · see citing works
“, stimulates the production of inflammatory cytokines) in response to Aβ plaques and tau tangles (94, 95).”
BackgroundInterleukin-1, neuroinflammation, and Alzheimer's disease
Mrak, R. E. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00287-1 · Cited by 356 · cited 1× · see citing works
“Similarly to TNF-α, also the proinflammatory cytokine IL-1β mediates the synaptotoxic effects of Aβ peptide (140).”
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× · see citing works
“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 · see citing works
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 · see citing works
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× · see citing works
“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…”
MethodBisht, K., Sharma, K. P., & Tremblay, M. (2018) · Neurobiology of Stress · doi:10.1016/j.ynstr.2018.05.003 · Cited by 351 · cited 1× · see citing works
“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).”
BackgroundThe role of astroglia in Alzheimer's disease: pathophysiology and clinical implications
Arranz, A. M., & Strooper, B. D. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30490-3 · Cited by 348 · see citing works
Exercise, inflammation and aging.
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LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide
Liu, Y., Walter, S., Stagi, M., Cherny, D., Letièmbre, M., Schulz‐Schaeffer, W., Heine, H., Penke, B., Neumann, H., & Fassbender, K. C. (2005) · Brain · doi:10.1093/brain/awh531 · Cited by 344 · see citing works
Reactive 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 340 · see citing works
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× · see citing works
“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).”
BackgroundPhysical Activity and Hemostatic and Inflammatory Variables in Elderly Men
Wannamethee, S. G. (2002) · Circulation · doi:10.1161/hc1502.107117 · Cited by 296 · see citing works
Cannabinoid 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 293 · see citing works
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 · see citing works
Inflammatory mechanisms in Alzheimer's disease
Eikelenboom, P., Zhan, S., van Gool, W. A., & Allsop, D. (1994) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(94)90057-4 · Cited by 291 · cited 1× · see citing works
“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 · see citing works
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 289 · see citing works
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 283 · cited 1× · see citing works
“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).”
BackgroundAstrocyte senescence: Evidence and significance
Cohen, J., & Torres, C. (2019) · Aging Cell · doi:10.1111/acel.12937 · Cited by 281 · see citing works
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 274 · cited 1× · see citing works
“Extracellular vesicles—constituted by microvesicles and exosomes and released by reactive microglia—play a role in AD pathogenesis (64) (Figure 1).”
BackgroundGlial 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 · see citing works
Endocrine Crosstalk Between Skeletal Muscle and the Brain
Delezie, J., & Handschin, C. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00698 · Cited by 270 · see citing works
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× · see citing works
“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…”
BackgroundMcAlpine, 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 269 · see citing works
Amyloid 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 · see citing works
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 · see citing works
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 249 · see citing works
Oosterhof, 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× · see citing works
“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 · see citing works
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 237 · see citing works
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 236 · cited 1× · see citing works
“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).”
BackgroundIntersection 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 · see citing works
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× · see citing works
“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 229 · see citing works
Interleukin-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 · see citing works
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× · see citing works
“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).”
BackgroundKotilinek, 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 220 · cited 1× · see citing works
“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).”
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× · see citing works
“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
Tarkowski, E., Liljeroth, A.-M., Minthon, L., Tarkowski, A., Wallin, A., & Blennow, K. (2003) · Brain Research Bulletin · doi:10.1016/s0361-9230(03)00088-1 · Cited by 219 · cited 1× · see citing works
“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).”
BackgroundKiyota, 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 216 · cited 1× · see citing works
“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 214 · see citing works
Clarke, J. R., Lyra e Silva, N. M., Figueiredo, C. P., Frozza, R. L., Ledo, J. H., Beckman, D., Katashima, C. K., Razolli, D., Carvalho, B. M., Frazão, R., et al. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201404183 · Cited by 214 · cited 1× · see citing works
“Aβ oligomeric forms prompt peripheral glucose intolerance in mice by activating TNF-α signaling in the hypothalamus (120).”
BackgroundLu, 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 214 · see citing works
Fan, Z., Aman, Y., Ahmed, I., Chetelat, G., Landeau, B., Ray Chaudhuri, K., Brooks, D. J., & Edison, P. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.06.016 · Cited by 212 · cited 2× · see citing works
“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.”
Backgroundvan Gool, W. A., Weinstein, H. C., Scheltens, P., & Walstra, G. J. M. (2001) · The Lancet · doi:10.1016/s0140-6736(01)05623-9 · Cited by 210 · see citing works
18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy
Passamonti, L., Rodríguez, P. V., Hong, Y. T., Allinson, K. S. J., Williamson, D., Borchert, R. J., Sami, S. A. K., Cope, T., Bevan-Jones, W. R., Jones, P. S., et al. (2016) · Brain · doi:10.1093/brain/aww340 · Cited by 207 · see citing works
Inflammatory biomarkers in Alzheimer's disease plasma
Morgan, A. R., Touchard, S., Leckey, C. A., O’Hagan, C., Nevado‐Holgado, A. J., Barkhof, F., Bertram, L., Blin, O. J., Bos, I., Dobričić, V., et al. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.03.007 · Cited by 207 · see citing works
Nicoll, J. A. R., Buckland, G. R., Harrison, C. H., Page, A. M., Harris, S., Love, S., Neal, J., Holmes, C., & Boche, D. (2019) · Brain · doi:10.1093/brain/awz142 · Cited by 205 · cited 1× · see citing works
“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).”
BackgroundAdult-derived neural precursors transplanted into multiple regions in the adult brain
Herrera, D. G., García‐Verdugo, J. M., & Álvarez-Buylla, A. (1999) · Annals of Neurology · doi:10.1002/1531-8249(199912)46:6 · Cited by 204 · see citing works
Immune Players in the CNS: The Astrocyte
Jensen, C., Massie, A., & Keyser, J. D. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9480-6 · Cited by 203 · cited 3× · see citing works
“The Role of Astrocytes Astrocytes, differently from microglia and similarly to neurons and oligodendrocytes, arise from the neuroectoderm (74).”
BackgroundInfluentialSekar, S., McDonald, J., Cuyugan, L., Aldrich, J., Kurdoglu, A., Adkins, J., Serrano, G., Beach, T. G., Craig, D. W., Valla, J., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.09.027 · Cited by 199 · cited 1× · see citing works
“Like microglia, astrocytes are also activated by tissue injury, infection, and inflammation (84).”
BackgroundParbo, P., Ismail, R., Hansen, K. V., Amidi, A., Mårup, F. H., Gottrup, H., Brændgaard, H., Eriksson, B. O., Eskildsen, S. F., Lund, T. E., et al. (2017) · Brain · doi:10.1093/brain/awx120 · Cited by 199 · see citing works
Alzheimer’s Disease, Oligomers, and Inflammation
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Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology
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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).”
BackgroundSun, Y., Minthon, L., Wallmark, A., Warkentin, S., Blennow, K., & Janciauskiene, S. M. (2003) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000071001 · Cited by 178 · see citing works
NSAID Exposure and Risk of Alzheimer's Disease: An Updated Meta-Analysis From Cohort Studies
Zhang, C., Wang, Y., Wang, D., Zhang, J., & Zhang, F. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00083 · Cited by 175 · see citing works
Randomized pilot study of nimesulide treatment in Alzheimer’s disease
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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× · see citing works
“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-citationMicroglial 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 167 · see citing works
Early 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 164 · cited 2× · see citing works
“CNS inflammation as an encouraging target to prevent the advancement of the pathology (19).”
BackgroundSelf-citationNielsen, H. M., Mulder, S. D., Beliën, J. A. M., Musters, R. J. P., Eikelenboom, P., & Veerhuis, R. (2010) · Glia · doi:10.1002/glia.21004 · Cited by 164 · see citing works
Increased 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× · see citing works
“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).”
BackgroundSelf-citationInflammatory 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 · see citing works
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 159 · cited 1× · see citing works
“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-citationMacPherson, K. P., Sompol, P. M., Kannarkat, G. T., Chang, J., Sniffen, L. J., Wildner, M., Norris, C. M., & Tansey, M. G. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.02.010 · Cited by 158 · see citing works
Zalevsky, J., Sécher, T., Ezhevsky, S. A., Janot, L., Steed, P. M., O’Brien, C., Eivazi, A., Kung, J., Nguyen, D.-H. T., Doberstein, S. K., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.3.1872 · Cited by 157 · see citing works
O’Bryant, S. E., Xiao, G., Barber, R. C., Huebinger, R. M., Wilhelmsen, K. C., Edwards, M., Graff‐Radford, N. R., Doody, R. S., Diaz-Arrastia, R. R., & Initiative, A. D. N. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028092 · Cited by 156 · see citing works
Tronel, C., Largeau, B., Ribeiro, M. J., Guilloteau, D., Dupont, A.-C., & Arlicot, N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040802 · Cited by 154 · cited 1× · see citing works
“Finally, there are other molecular targets that can offer a more exhaustive depiction of in vivo neuroinflammation (200).”
BackgroundChen, J.-H., Ke, K.-F., Lu, J.-H., Qiu, Y.-H., & Peng, Y.-P. (2015) · PLOS ONE · doi:10.1371/journal.pone.0116549 · Cited by 151 · cited 1× · see citing works
“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 · see citing works
Peripheral Inflammatory Cytokines as Biomarkers in Alzheimer’s Disease and Mild Cognitive Impairment
Guerreiro, R. J., Santana, I. J., Brás, J., Santiago, B., Paiva, A. A., & Oliveira, C. R. (2007) · Neurodegenerative Diseases · doi:10.1159/000107700 · Cited by 150 · cited 15× · see citing works
“Actually, a trial recruiting MCI individuals highlights that rofecoxib could rush the conversion to AD (223).”
BackgroundInfluentialAmyloid 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 148 · cited 1× · see citing works
“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…”
BackgroundSelf-citationMhatre, M., Floyd, R. A., & Hensley, K. (2004) · Journal of Alzheimer s Disease · doi:10.3233/jad-2004-6206 · Cited by 147 · cited 1× · see citing works
“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× · see citing works
“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).”
BackgroundExercise 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 146 · see citing works
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 145 · cited 1× · see citing works
“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).”
BackgroundKlein, W. L. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129039 · Cited by 141 · see citing works
Long-Term Efficacy and Safety of Celecoxib in Alzheimer’s Disease
Soininen, H. S., West, C. R., Robbins, J. L., & Niculescu, L. (2006) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000096588 · Cited by 141 · see citing works
A 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× · see citing works
“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 · see citing works
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 138 · cited 4× · see citing works
“Neuroinflammatory pathways and microglial cells activation are associated with neuronal ectopic cell cycle activation (105).”
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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 137 · see citing works
β‐amyloid inhibition of long‐term potentiation is mediated via tumor necrosis factor
Wang, Q., Wu, J., Rowan, M. J., & Anwyl, R. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04457.x · Cited by 133 · cited 1× · see citing works
“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).”
ResultGuo, L., Bertola, D. R., Takanohashi, A., Saito, A., Segawa, Y., Yokota, T., Ishibashi, S., Nishida, Y., Yamamoto, G. L., Franco, J. F. D. S., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.03.004 · Cited by 133 · see citing works
Caruso, G., Fresta, C. G., Musso, N., Giambirtone, M., Grasso, M., Spampinato, S. F., Merlo, S., Drago, F., Lazzarino, G., Sortino, M. A., et al. (2019) · Cells · doi:10.3390/cells8010064 · Cited by 129 · see citing works
Self-citationTargeting TNF: a therapeutic strategy for Alzheimer's disease
Cheng, X., Shen, Y., & Li, R. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.06.029 · Cited by 128 · cited 1× · see citing works
“Among the different mediators of inflammation explored, TNFα mediates proinflammatory processes in various ND including AD (136).”
BackgroundInferring relevant cell types for complex traits by using single-cell gene expression
Calderon, D., Bhaskar, A., Knowles, D. A., Golan, D., Raj, T., Fu, A. Q., & Pritchard, J. K. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.09.009 · Cited by 127 · see citing works
A 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 126 · cited 7× · see citing works
“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).”
BackgroundInfluentialSelf-citationCellular, synaptic, and biochemical features of resilient cognition in Alzheimer’s disease
Arnold, S. E., Louneva, N., Cao, K., Wang, L.-S., Han, L.-Y., Wolk, D. A., Negash, S., Leurgans, S. E., Schneider, J. A., Buchman, A. S., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.03.004 · Cited by 123 · see citing works
Effect of Exercise on Inflammatory Profile of Older Persons: Systematic Review and Meta-Analyses
Monteiro-Júnior, R. S., Maciel-Pinheiro, P. D. T., Portugal, E. M. M., Figueiredo, L. F. D. S., Terra, R., Carneiro, L. S. R. D. S. F., Rodrigues, V. D., Nascimento, O. J. M., Deslandes, A. C., & Laks, J. (2017) · Journal of Physical Activity and Health · doi:10.1123/jpah.2016-0735 · Cited by 123 · see citing works
Varvel, N. H., Bhaskar, K., Kounnas, M. Z., Wagner, S. L., Yang, Y., Lamb, B. T., & Herrup, K. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39716 · Cited by 121 · cited 3× · see citing works
“Abbreviations: [11C]-PIB, [11C]-Pittsburgh compound-B; [18F]fluorodeoxyglucose-PET, [18F]-fluorodeoxyglucose-positron emission tomography; Aβ, amyloid beta; Aβ1−40, 40-amino acid-long amyloid beta peptide; Aβ1−42, 42-amino acid-long amyloid beta peptide; AD, Alzheimer’s disease; ADAPT, Alzheimer’s disease anti-inflamm…”
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Shen, 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 · see citing works
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
Liang, T., Zhang, Y., Wu, S., Chen, Q., & Wang, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.845185 · Cited by 220 · see citing works
Role of Inflammatory Processes in Hemorrhagic Stroke
Ohashi, S. N., DeLong, J. H., Kozberg, M. G., Mazur-Hart, D. J., van Veluw, S. J., Alkayed, N. J., & Sansing, L. H. (2023) · Stroke · doi:10.1161/strokeaha.122.037155 · Cited by 217 · see citing works
The role of innate immune genes in Alzheimer's disease
Griciuc, A., & Tanzi, R. E. (2021) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000911 · Cited by 191 · see citing works
“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].”
BackgroundSahu, M., Gupta, R. V., Ambasta, R. K., & Kumar, P. (2022) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2022.03.002 · Cited by 202 · see citing works
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Role of JAK/STAT in the Neuroinflammation and its Association with Neurological Disorders
Jain, M., Singh, M. K., Shyam, H., Mishra, A., Kumar, S., Kumar, A., & Kushwaha, J. K. (2021) · Annals of Neurosciences · doi:10.1177/09727531211070532 · Cited by 189 · see citing works
Versele, R., Sevin, E., Gosselet, F., Fénart, L., & Candela, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810235 · Cited by 172 · see citing works
Neuroinflammation: A Potential Risk for Dementia
Ahmad, M. A., Kareem, O., Khushtar, M., Akbar, M., Haque, M. R., Iqubal, A., Haider, M. F., Pottoo, F. H., Abdulla, F. S., Al-Haidar, M. B., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020616 · Cited by 163 · see citing works
Glia Crosstalk in Neuroinflammatory Diseases
Bernaus, A., Blanco, S., & Sevilla, A. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00209 · Cited by 157 · see citing works
The foundation and architecture of precision medicine in neurology and psychiatry
Hampel, H. J., Gao, P., Cummings, J. L., Toschi, N., Thompson, P. M., Hu, Y., Cho, M., & Vergallo, A. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2022.12.004 · Cited by 149 · see citing works
“The temporal-spatial dynamics of the neuroinflammatory process could be dissected through multi-omics profiling along with neuroimaging and could potentially be targeted by specific and stage-guided immune-modulator drugs, such as TREM2 agonists, to modify disease progression [157,158].”
Self-citationThe Alzheimer’s disease drug development landscape
van Bokhoven, P., de Wilde, A., Vermunt, L., Leferink, P. S., Heetveld, S., Cummings, J., Scheltens, P., & Vijverberg, E. G. B. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00927-z · Cited by 123 · see citing works
“Targeting pathways involved in (neuro)inflammation remains a strategy of interest both in preclinical and clinical development [11].”
BackgroundThe Future of Precision Medicine in the Cure of Alzheimer’s Disease
Arafah, A., Khatoon, S., Rasool, I., Khan, A., Rather, M. A., Abujabal, K. A., Faqih, Y. A. H., Rashid, H., Rashid, S. M., Bilal Ahmad, S., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11020335 · Cited by 133 · see citing works
Astrocyte biomarkers GFAP and YKL‐40 mediate early Alzheimer's disease progression
Pelkmans, W., Shekari, M., Brugulat‐Serrat, A., Sánchez‐Benavides, G., Minguillón, C., Fauria, K., Molinuevo, J. L., Grau‐Rivera, O., González Escalante, A., Kollmorgen, G., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13450 · Cited by 122 · see citing works
Exploring ER stress response in cellular aging and neuroinflammation in Alzheimer's disease
Uddin, M. S., Yu, W. S., & Lim, L. W. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101417 · Cited by 118 · see citing works
Dhiman, K., Blennow, K., Zetterberg, H., Martins, R. N., & Gupta, V. B. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03040-5 · Cited by 114 · see citing works
The role of the immune system in Alzheimer’s disease
Wu, K., Zhang, Y.-R., Huang, Y., Dong, Q., Tan, L., & Yu, J. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101409 · Cited by 116 · see citing works
Wang, W., Wang, Y., Wang, Y., Xie, G., Liu, S., Li, Z., Wang, P., Liu, J., & Li, L. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155518 · Cited by 107 · see citing works
Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings
de Oliveira, J., Kucharska, E., Garcez, M. L., Rodrigues, M. S., Quevedo, J., Moreno‐González, I., & Budni, J. (2021) · Cells · doi:10.3390/cells10102581 · Cited by 105 · see citing works
Alzheimer's disease pathophysiology in the Retina
Gaire, B. P., Koronyo, Y., Fuchs, D.-T. S., Shi, H., Rentsendorj, A., Danziger, R., Vit, J., Mirzaei, N., Doustar, J., Sheyn, J., et al. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2024.101273 · Cited by 102 · see citing works
Self-citationmicroRNA-Based Biomarkers in Alzheimer’s Disease (AD)
Zhao, Y., Jaber, V. R., Alexandrov, P. N., Vergallo, A., Lista, S., Hampel, H. J., & Lukiw, W. J. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.585432 · Cited by 98 · see citing works
Self-citationAlzheimer’s Disease and Inflammaging
Kosyreva, A., Sentyabreva, A., Tsvetkov, I., & Makarova, O. (2022) · Brain Sciences · doi:10.3390/brainsci12091237 · Cited by 98 · see citing works
Neuroinflammation, Its Role in Alzheimer's Disease and Therapeutic Strategies
Király, M., Foss, J. F., & Giordano, T. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.109 · Cited by 103 · see citing works
“Details on the role of microglia in AD, alternative pathways that contribute to their activation to various degrees in between the M1 and M2 states (including NF-κB, mTOR, MAPK, proinflammatory mediators, interleukins, anti-inflammatory cytokines, complement proteins, chemokines, caspases, prostanoids, neuroprotection…”
BackgroundBlood–brain barrier leakage and perivascular inflammation in cerebral amyloid angiopathy
Kozberg, M. G., Yi, I., Freeze, W. M., Auger, C. A., Scherlek, A. A., Greenberg, S. M., & van Veluw, S. J. (2022) · Brain Communications · doi:10.1093/braincomms/fcac245 · Cited by 94 · see citing works
Targeting Cytokine-Mediated Inflammation in Brain Disorders: Developing New Treatment Strategies
Mallick, R., Basak, S., Chowdhury, P., Bhowmik, P., Das, R. K., Banerjee, A., Paul, S., Pathak, S., & Duttaroy, A. K. (2025) · Pharmaceuticals · doi:10.3390/ph18010104 · Cited by 94 · see citing works
“Personalized techniques can enhance therapeutic results by targeting interventions to patients most likely to benefit from cytokine regulation [94–96].”
The immune system on the TRAIL of Alzheimer’s disease
Burgaletto, C., Munafò, A., Benedetto, G. D., Francisci, C. D., Caraci, F., Mauro, R. D., Bucolo, C., Bernardini, R., & Cantarella, G. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01968-1 · Cited by 92 · see citing works
Self-citationNeuroinflammation as a Potential Therapeutic Target in Alzheimer’s Disease
Liu, P., Wang, Y., Sun, Y., & Peng, G. (2022) · Clinical Interventions in Aging · doi:10.2147/cia.s357558 · Cited by 92 · see citing works
“rivastigmine) and non-competitive N-methyl-D-aspartate antagonists (memantine); these compounds can only temporarily alleviate symptoms already apparent in the dementia stage.(6) Although more than 99% of AD drug trials do not meet efficacy endpoints, the first Phase 3 clinical trial of sodium oligomannate (GV-971) wa…”
BackgroundRen, F., Wei, J., Chen, Q., Hu, M., Yu, L., Mi, J., Zhou, X., Qin, D., Wu, J., & Wu, A. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.07.030 · Cited by 97 · see citing works
Torrisi, S. A., Geraci, F., Tropea, M. R., Grasso, M., Caruso, G., Fidilio, A., Musso, N., Sanfilippo, G., Tascedda, F., Palmeri, A., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00693 · Cited by 86 · see citing works
Self-citationWang, S., Ma, J., Zeng, Y., Zhou, G., Wang, Y., Zhou, W., Sun, X., & Wu, M. (2021) · Drug Design Development and Therapy · doi:10.2147/dddt.s310686 · Cited by 85 · see citing works
Song, J. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114647 · Cited by 84 · see citing works
Tesco, G., & Lomoio, S. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101628 · Cited by 91 · see citing works
Lista, S., Imbimbo, B. P., Grasso, M., Fidilio, A., Emanuele, E., Minoretti, P., López-Ortiz, S., Martín-Hernández, J., Gabelle, A., Caruso, G., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03163-y · Cited by 81 · see citing works
“Therefore, identifying TREM2 carriers can be valuable in improving patient stratification for clinical trials and supporting the development of personalized therapeutic approaches [33].”
BackgroundSelf-citationHeneka, M., Gauthier, S., Chandekar, S. A., Hahn-Pedersen, J. H., Bentsen, M. A., & Zetterberg, H. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-02939-9 · Cited by 84 · see citing works
Anti-amyloid-β protein agents for the treatment of Alzheimer’s disease: an update on emerging drugs
Lozupone, M., Solfrizzi, V., D’Urso, F., Di Gioia, I., Sardone, R., Dibello, V., Stallone, R., Liguori, A., Ciritella, C., Daniele, A., et al. (2020) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2020.1808621 · Cited by 77 · see citing works
The Potential Role of Cytokines and Growth Factors in the Pathogenesis of Alzheimer’s Disease
Ogunmokun, G., Dewanjee, S., Chakraborty, P., Valupadas, C., Chaudhary, A., Kolli, V., Anand, U., Vallamkondu, J., Goel, P., Paluru, H. P. R., et al. (2021) · Cells · doi:10.3390/cells10102790 · Cited by 85 · see citing works
Do, H., & Cho, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176211 · Cited by 63 · see citing works
Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders
Malar, D. S., Thitilertdecha, P., Ruckvongacheep, K. S., Brimson, S., Tencomnao, T., & Brimson, J. M. (2023) · CNS Drugs · doi:10.1007/s40263-023-01007-6 · Cited by 74 · see citing works
“The key components of the disease have been reported to be the accumulation of amyloid precursor protein (APP) fragment amyloidbeta (Aβ) from its overproduction or reduced clearance [35], and the downstream process in hyperphosphorylation of the protein tau, leading to cell death, neurotransmitter deficits [36], reduc…”
BackgroundTargeting NLRP3-Mediated Neuroinflammation in Alzheimer’s Disease Treatment
Barczuk, J., Siwecka, N., Lusa, W., Rozpędek‐Kamińska, W., Kucharska, E., & Majsterek, I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168979 · Cited by 75 · see citing works
CD33 isoforms in microglia and Alzheimer's disease: Friend and foe
Eskandari‐Sedighi, G., Jung, J., & Macauley, M. S. (2022) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2022.101111 · Cited by 68 · see citing works
Brain Structural and Functional Changes in Cognitive Impairment Due to Alzheimer’s Disease
Ávila‐Villanueva, M., Dolado, A. M., Gómez‐Ramírez, J., & Fernández‐Blázquez, M. A. (2022) · Frontiers in Psychology · doi:10.3389/fpsyg.2022.886619 · Cited by 67 · see citing works
Current and evolving treatment strategies for the Alzheimer disease continuum
Marasco, R. (2020) · The American Journal of Managed Care · doi:10.37765/ajmc.2020.88481 · Cited by 65 · see citing works
Neuroinflammation PET imaging of the translocator protein (TSPO) in Alzheimer's disease: An update
Gouilly, D., Saint‐Aubert, L., Ribeiro, M. J., Salabert, A., Tauber, C., Péran, P., Arlicot, N., Pariente, J., & Payoux, P. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15613 · Cited by 66 · see citing works
“These results have driven the development of biomarkers to improve our understanding of AD neuroimmune changes and to monitor the engagement of inflammatory treatments (Gyengesi & Münch, 2020; Hampel et al., 2020).”
BackgroundTargeting Microglia-Synapse Interactions in Alzheimer’s Disease
Piccioni, G., Mango, D., Saidi, A., Corbo, M., & Nisticò, R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052342 · Cited by 62 · see citing works
Self-citationThe road to precision medicine: Eliminating the “One Size Fits All” approach in Alzheimer’s disease
Behl, T., Kaur, I., Sehgal, A., Singh, S., Albarrati, A., Albratty, M., Najmi, A., Meraya, A. M., & BUNGAU, S. G. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113337 · Cited by 64 · see citing works
Gertje, E. C., Janelidze, S., van Westen, D., Cullen, N. C., Stomrud, E., Palmqvist, S., Hansson, O., & Mattsson, N. (2023) · Neurology · doi:10.1212/wnl.0000000000207113 · Cited by 62 · see citing works
Locus Coeruleus Modulates Neuroinflammation in Parkinsonism and Dementia
Giorgi, F. S., Biagioni, F., Galgani, A., Pavese, N., Lazzeri, G., & Fornai, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228630 · Cited by 59 · see citing works
Fernando, K., & Wijayasinghe, Y. S. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.746631 · Cited by 57 · see citing works
Rapamycin Responds to Alzheimer’s Disease: A Potential Translational Therapy
Hou, S.-J., Zhang, S., Li, Y., & Xu, S.-Y. (2023) · Clinical Interventions in Aging · doi:10.2147/cia.s429440 · Cited by 58 · see citing works
“Hyperphosphorylated tau protein aggregates form paired helical filaments in NFTs as one of the key hallmarks of AD.”
InfluentialMenopause hormone therapy significantly alters pathophysiological biomarkers of Alzheimer's disease
Depypere, H. T., Vergallo, A., Lemercier, P., Lista, S., Benedet, A. L., Ashton, N. J., Cavedo, E., Zetterberg, H., Blennow, K., Vanmechelen, E., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12759 · Cited by 60 · see citing works
Self-citationZhang, W., Hua, H., Guo, Y., Cheng, Y., Pi, F., Yao, W., Xie, Y., & He, Q. (2020) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.0c01892 · Cited by 55 · see citing works
Role of TREM2 in Alzheimer’s Disease: A Long Road Ahead
Kulkarni, B., Kumar, D., Martins, N. A., & Sellamuthu, S. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02477-9 · Cited by 52 · see citing works
Wyatt-Johnson, S. K., & Brutkiewicz, R. R. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.592359 · Cited by 50 · see citing works
Hampel, H. J., Goetzl, E. J., Kapogiannis, D., Lista, S., & Vergallo, A. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00310 · Cited by 47 · see citing works
Self-citationBarber, K., Mendonca, P., & Soliman, K. F. A. (2023) · Brain Sciences · doi:10.3390/brainsci13010145 · Cited by 50 · see citing works
“tify the target group and provide the process, contributed to the disappointing results [36].”
BackgroundInfluentialZhang, L., Wang, X., Yu, W., Ying, J., Fang, P., Zheng, Q., Feng, X., Hu, J., Xiao, F., Chen, S., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.836494 · Cited by 46 · see citing works
Alzheimer’s Disease: From Immune Homeostasis to Neuroinflammatory Condition
Cariddi, L. P., Mauri, M. F., Cosentino, M., Versino, M., & Marino, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113008 · Cited by 45 · see citing works
Calmodulin binding proteins and neuroinflammation in multiple neurodegenerative diseases
O’Day, D. H., & Huber, R. J. (2022) · BMC Neuroscience · doi:10.1186/s12868-022-00695-y · Cited by 42 · see citing works
“Here, we examined proteins identified by others that are critical to neuroinflammation and other neurodegenerative events involved not only in AD but also in HD, LBD, PD, FTD, MS and other neurodegenerative diseases [18, 19, 22, 50].”
BackgroundBrain targeting based nanocarriers loaded with resveratrol in Alzheimer's disease: A review
Jalili, C., Kiani, A., Gholami, M., Bahrehmand, F., Fakhri, S., Kakehbaraei, S., & Kakebaraei, S. (2023) · IET Nanobiotechnology · doi:10.1049/nbt2.12127 · Cited by 42 · see citing works
“Neuroinflammation has a crucial impress in the induction of AD [84].”
BackgroundYu, W.-Y., Sun, T.-H., Hsu, K.-C., Wang, C., Chien, S.-Y., Tsai, C., & Yang, Y. (2024) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2024.108621 · Cited by 40 · see citing works
Roles of TREM2 in the Pathological Mechanism and the Therapeutic Strategies of Alzheimer's Disease
Lin, M., Yu, J., Zhang, W., Lao, F., & Huang, H. (2024) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2024.164 · Cited by 41 · see citing works
Alzheimer Disease Occurs More Frequently In Patients With Inflammatory Bowel Disease
Aggarwal, M., Alkhayyat, M. M., Saleh, M. A., Sarmini, M. T., Singh, A., Garg, R., Garg, P., Mansoor, E., Padival, R., & Cohen, B. L. (2022) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0000000000001714 · Cited by 40 · see citing works
Hao, Y., Su, C., Liu, X., Sui, H., Shi, Y., & Zhao, L. (2022) · Biomaterials Advances · doi:10.1016/j.bioadv.2022.212770 · Cited by 39 · see citing works
CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases
Goldsteins, G., Hakosalo, V., Jaronen, M., Keuters, M. H., Lehtonen, Š., & Koıstınaho, J. (2022) · Antioxidants · doi:10.3390/antiox11020405 · Cited by 40 · see citing works
Associations between saliva and plasma cytokines in cognitively normal, older adults
Parkin, G. M., Kim, S., Mikhail, A. P., Malhas, R., McMillan, L. C., Hollearn, M. K., Granger, D. A., Mapstone, M. E., Yassa, M. A., & Thomas, E. A. (2022) · Aging Clinical and Experimental Research · doi:10.1007/s40520-022-02292-9 · Cited by 38 · see citing works
“We also measured levels of YKL-40, a pro-inflammatory glycoprotein, which has been considered as a pleiotropic cytokine given its secretion by macrophages and involvement in a wide range of inflammatory responses [26, 27] neuroinflammation and astroglial activation [28, 29].”
BackgroundThrombin, a Key Driver of Pathological Inflammation in the Brain
Iannucci, J., & Grammas, P. (2023) · Cells · doi:10.3390/cells12091222 · Cited by 38 · see citing works
“Therefore, targeting inflammation is a rational approach to AD prevention and therapy [141].”
BackgroundPET Agents in Dementia: An Overview
van Waarde, A., Marcolini, S., Deyn, P. P. D., & Dierckx, R. (2021) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2020.12.008 · Cited by 38 · see citing works
Knorr, U., Simonsen, A., Jensen, C. S., Zetterberg, H., Blennow, K., Akhøj, M., Forman, J., Hasselbalch, S., & Kessing, L. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.10.074 · Cited by 34 · see citing works
Kirubakaran, D. (2025) · Digital Chinese Medicine · doi:10.1016/j.dcmed.2025.05.002 · Cited by 38 · see citing works
The chaperone Clusterin in neurodegeneration−friend or foe?
Yuste‐Checa, P., Bracher, A., & Hartl, F. U. (2022) · BioEssays · doi:10.1002/bies.202100287 · Cited by 36 · see citing works
“response, providing support for the critical role of neuroinflammation in AD pathogenesis.[131] An upregulation of inflammation-related”
BackgroundTherapeutic Targeting Strategies for Early- to Late-Staged Alzheimer’s Disease
Kang, Y. J., Diep, Y. N., Tran, M., & Cho, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249591 · Cited by 36 · see citing works
Astrocyte subtype-specific approach to Alzheimer's disease treatment
Sarkar, S., & Biswas, S. C. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104956 · Cited by 34 · see citing works
Carthamus tinctorius L.: A natural neuroprotective source for anti-Alzheimer's disease drugs
Liang, Y., & Wang, L. (2022) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2022.115656 · Cited by 33 · see citing works
A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice
Balu, D., Valencia‐Olvera, A. C., Nguyen, A. Q., Patnam, M., York, J. M., Peri, F., Neumann, F., LaDu, M. J., & Tai, L. M. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01330-6 · Cited by 32 · see citing works
Frye, B. M., Craft, S., Latimer, C. S., Keene, C. D., Montine, T. J., Register, T. C., Orr, M. E., Kavanagh, K., Macauley, S. L., & Shively, C. A. (2021) · American Journal of Primatology · doi:10.1002/ajp.23260 · Cited by 32 · see citing works
“, 2011), which are hypothesized to contribute to AD-like pathophysiologic processes (Hampel et al., 2020; Hashemiaghdam & Mroczek, 2020).”
BackgroundBoosting mitochondrial health to counteract neurodegeneration
Burtscher, J., Romani, M., Bernardo, G., Popa, T., Ziviani, E., Hummel, F. C., Sorrentino, V., & Millet, G. P. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102289 · Cited by 34 · see citing works
Microglial autophagy in Alzheimer’s disease and Parkinson’s disease
Wang, Z., Wang, Q., Li, S., Li, X.-J., Yang, W., & He, D. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1065183 · Cited by 35 · see citing works
Discontinued disease-modifying therapies for Alzheimer’s disease: status and future perspectives
Imbimbo, B. P., Lozupone, M., Watling, M., & Panza, F. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1795127 · Cited by 31 · see citing works
Self-citationYan, Y., Aierken, A., Wang, C., Song, D. F., Ni, J., Wang, Z., Quan, Z., & Qing, H. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.11.009 · Cited by 32 · see citing works
A dynamical systems approach for multiscale synthesis of Alzheimer’s pathogenesis
Rollo, J. L., Crawford, J. W., & Hardy, J. (2023) · Neuron · doi:10.1016/j.neuron.2023.04.018 · Cited by 30 · see citing works
“A systems approach will therefore lead to more effective personalised plans in the treatment of the neuroinflammatory mechanisms in AD 69 studying the disease’s progression over time with a dynamical systems approach, will better inform these therapeutic strategies.”
DYRK1A Inhibitors and Perspectives for the Treatment of Alzheimer's Disease
de Souza, M. M., Cenci, A. R., Teixeira, K. F., Machado, V., Schülerb, M. C. G. M., Gonçalves, A. E., Dalmagro, A. P., Cazarin, C. A., Ferreira, L. L. G., de Oliveira, A. S., et al. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220620162018 · Cited by 30 · see citing works
Therapeutics of Alzheimer’s Disease: Recent Developments
Burns, S., Selman, A., Sehar, U., Rawat, P., Reddy, A. P., & Reddy, P. H. (2022) · Antioxidants · doi:10.3390/antiox11122402 · Cited by 31 · see citing works
“Dominant-negative TNF inhibitors, such as XPro®1595 [67] and XENP 345 [68], are considered effective therapeutics for targeting TNF. AL002, a humanized monoclonal IgG1 antibody, is an anti-human TREM2 antibody under phase 2 study; phase 1 study data suggested it to be safe and tolerable by healthy adults [78].”
BackgroundInfluentialNavigating the dementia landscape: Biomarkers and emerging therapies
Maheshwari, S., Singh, A., Ansari, V. A., Mahmood, T., Wasim, R., Akhtar, J., & Verma, A. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102193 · Cited by 30 · see citing works
Antonioni, A., Martorana, A., Santarnecchi, E., Hampel, H. J., & Koch, G. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70337 · Cited by 31 · see citing works
Self-citationA Therapeutic Strategy for Alzheimer's Disease Focused on Immune-inflammatory Modulation
Kim, S. H., Noh, M., Kim, H.-J., Oh, K., Park, J., Lee, S.-G., Moon, Y., Kim, Y.-E., Bae, J. S., Jin, H. K., et al. (2019) · Dementia and Neurocognitive Disorders · doi:10.12779/dnd.2019.18.2.33 · Cited by 30 · see citing works
Rasouli, H., Nayeri, F. D., & Khodarahmi, R. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.981984 · Cited by 30 · see citing works
Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia
Pase, M. P., Himali, J. J., Puerta, R., Beiser, A., Gonzales, M. M., Satizábal, C. L., Yang, Q., Aparicio, H. J., Kojis, D. J., DeCarli, C. S., et al. (2024) · Neurology · doi:10.1212/wnl.0000000000208075 · Cited by 29 · see citing works
Targeting Abnormal Tau Phosphorylation for Alzheimer’s Therapeutics
Singh, A., Ansari, V. A., Mahmood, T., Hasan, S. S., Wasim, R., Maheshwari, S., Akhtar, J., Sheikh, S., & Vishwakarma, V. K. (2024) · Hormone and Metabolic Research · doi:10.1055/a-2238-1384 · Cited by 29 · see citing works
“Research has demonstrat - ed that AD patients have a substantial accumulation of tau protein in brain tissue compared to healthy control groups [10–15].”
BackgroundZhang, L., Liu, Y., Wang, X., Wang, D., Wu, H., Chen, H., Chen, J., & Liu, Y. (2022) · Physiology & Behavior · doi:10.1016/j.physbeh.2022.113820 · Cited by 27 · see citing works
Takata, K., Kimura, H., Yanagisawa, D., Harada, K., Nishimura, K., Kitamura, Y., Shimohama, S., & Tooyama, I. (2022) · Molecules · doi:10.3390/molecules27092780 · Cited by 29 · see citing works
“Neuroinflammation is a central pathogenic process in a variety of neurodegenerative diseases [72] and is one of the most important factors in the etiology of AD [73].”
BackgroundWątroba, M., & Szukiewicz, D. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.962769 · Cited by 29 · see citing works
Potential of food-derived bioactive peptides in alleviation and prevention of Alzheimer's disease
Zhao, L., Li, D., Qi, X., Guan, K., Chen, H., Wang, R., & Ma, Y. (2022) · Food & Function · doi:10.1039/d2fo02278h · Cited by 29 · see citing works
New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease
Li, N., Deng, M., Hu, G., Li, N., Yuan, H., & Zhou, Y. (2022) · Biomolecules · doi:10.3390/biom12111722 · Cited by 30 · see citing works
Zou, W., Liu, J., Jiao, Y., Sun, Y., Chen, N., Zhou, L., Guan, X., Wang, J., Wei, W., Han, C., et al. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.339002 · Cited by 28 · see citing works
“Studies have consistently demonstrated that disease-associated astrocytes (DAAs) respond to inflammatory damage by promoting release of inflammatory factors, which accelerate activation of astrocytes and microglia (Chávez et al., 2019; Wang et al., 2019; Hampel et al., 2020).”
BackgroundA Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis
Needham, H., Torpey, G., Flores, C. C., Davis, C. J., Vanderheyden, W. M., & Gerstner, J. R. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.798994 · Cited by 28 · see citing works
“Despite its likely beneficial role, overexpression of TREM2 is insufficient to ward off AD progression.”
BackgroundInfluentialYang, Y., Seok, M., Kim, Y. E., Choi, Y., Song, J., Sulistio, Y. A., Kim, S., Chang, M., Oh, S., Nam, M., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01693-6 · Cited by 28 · see citing works
“[2, 3]).”
Alzheimer’s Disease Treatment: The Search for a Breakthrough
Reiss, A. B., Muhieddine, D., Jacob, B., Mesbah, M., Pinkhasov, A., Gomolin, I. H., Stecker, M. M., Wısnıewskı, T., & Leon, J. D. (2023) · Medicina · doi:10.3390/medicina59061084 · Cited by 29 · see citing works
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“Nevertheless, these drugs provide only a temporary symptomatic relief, failing to improve the patients ’ cognitive function or to provide a de fi nitive cure [7].”
Beyond the amyloid cascade: An update of Alzheimer's disease pathophysiology
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- 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 · 2019: 5
- 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
- Health Sciences › Medicine › Physiology › 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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