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Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice
Open accessAbstract
Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of β-amyloid (Aβ) before formation of senile plaques. However, persistent Aβ accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Aβ may decrease with age and progression of AD pathology. To determine the effects of aging and Aβ deposition on microglial ability to clear Aβ, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the Aβ-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Aβ-degrading enzymes insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1β (interleukin-1β) and tumor necrosis factor α (TNFα), suggesting that there is an inverse correlation between cytokine production and Aβ clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFα decreased the expression of SRA and CD36 and reduced Aβ uptake. Our data indicate that, although early microglial recruitment promotes Aβ clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Aβ deposition downregulate genes involved in Aβ clearance and promote Aβ accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.
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“their phagocytic capacity declines with aging, chronic exposure to Αβ, and during sustained inflammation in the AD brain76,16,17.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, as AD progresses, microglia acquire a chronically activated phenotype through unremitting stimulation by cytokines and A itself, which compromises their clearance function (Bamberger et al., 2003;Hickman et al., 2008;Heneka et al., 2010a) .”
From PPARγ/RXRα-Induced and CD36-Mediated Microglial Amyloid-β Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice (2012) · cites this paper as Hickman et al., 2008
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Progression of Alzheimer's disease is associated with reduced Aβ-clearing pathways resulting in Aβ accumulation (4–6).”
From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Progression of Alzheimer's disease in humans and mouse models of the disease is associated with reduced expression of these Aβ-clearing enzymes resulting in decreased Aβ clearance and increased Aβ accumulation (5, 24).”
From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This impairment has been shown to correlate with increased production of proinflammatory cytokines and overwhelming accumulation of Aβ plaques in the AD brain [20–22].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [22]
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“Notably, previous studies have shown that microglial function may be adversely affected by Aβ, particularly as a result of chronic exposure to pro-inflammatory cytokines, resulting in increased Aβ accumulation and potentially underpinning the contradiction between our in vitro and in vivo results.39,40”
From Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [40]
The cited source says what the claim attributes to it.
In the citing paper
“Thus, endothelial expression of LRP1 promotes the clearance of Aβ across the BBB in vivo, a process directly modulated by PCSK9 inhibitor treatment (93, 94), and the expression of CD36 parallels the ability of microglia to perform Aβ clearance (95).”
From PCSK9 and the nervous system: a no-brainer? (2023) · cites this paper as [95]
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In the citing paper
“Increased pro-inflammatory gene expression in response to accumulating Αβ in older AD mice leads to decreased microglial Αβ clearance receptors or Αβ-degrading enzymes, thereby promoting further Αβ accumulation16.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [16]
The cited source says what the claim attributes to it.
In the citing paper
“the ability of microglia to remove Αβ declines over time”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [16]
The cited source says what the claim attributes to it.
In the citing paper
“supporting that the progression of amyloid pathology correlates with impaired capacity of microglia to phagocytose Αβ17,16.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [16]
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“As one of the most relevant consequences, the loss of microglial phagocytic capacity leads to further Aβ accumulation and aggregation, accelerating the progression of AD [17].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [17]
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In the citing paper
“We have previously shown that expression of IDE in microglia from PS1-APP mice decreases with age and progression of AD-like pathology (5).”
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In the citing paper
“Finally, Inpp5d was identified as a target of miR155, and constitutive deletion of miR155, which should increase SHIP1, led to an increase in amyloid plaques.40,41”
From Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [40]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Finally, Inpp5d was identified as a target of miR155, and constitutive deletion of miR155, which should increase SHIP1, led to an increase in amyloid plaques.40,41”
From Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [40]
Experimental — accuracy not yet measuredIn the citing paper
“Aged glial cells respond less efficiently to antigens, including amyloid-β (Aβ) and α-synuclein, and have reduced phagocytic and antiinflammatory capacity (161–163).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [161]
In the citing paper
“AD is accompanied by activation of microglia and astrocytes1,2 that affects the clearance and production of Aβ42,3,4 development and propagation of tau pathology,5 exacerbates neurodegeneration, and influences disease progression and severity.6,7”
From CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease (2018) · cites this paper as [3]
In the citing paper
“microglia from a mouse model of Aβ deposition (Aβ-mice) have reduced expression of Aβ-phagocytic receptors and Aβ-degrading enzymes, but their ability to produce proinflammatory cytokines was maintained6.”
From Microglia in neurodegeneration (2018) · cites this paper as [6]
In the citing paper
“In response to such stimuli, microglia can initiate a neuroinflammatory response which, like peripheral inflammation, includes production of cytokines such as TNF and IL-16,27, and possibly chemokines such as Ccl228, to recruit additional cells and induce them to clear injurious agents and maintain brain homeostasis.”
From Microglia in neurodegeneration (2018) · cites this paper as [6]
In the citing paper
“Aβ clearance involves, in part36, phagocytosis and endocytosis via microglial scavenger receptors (SRs)37,38 and extracellular degradation by Aβ-degrading enzymes6,36.”
From Microglia in neurodegeneration (2018) · cites this paper as [6]
In the citing paper
“Despite effective uptake, Aβ clearance by microglia in AD may be ineffective despite phagocytic uptake [55].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [55]
In the citing paper
“In AD, microglia cluster around beta-amyloid plaques highlighting their inability to clear beta-amyloid (Hickman et al., 2008; Liu et al., 2010).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Hickman et al., 2008
In the citing paper
“Immune involvement in neurodegenerative disease centres on findings that pro-inflammatory microglia are closely associated with protein aggregate pathologies characteristic of most dementias.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [13]
In the citing paper
“In Alzheimer’s disease (AD), the most common form of dementia, microglia surround amyloid plaques and respond to amyloid-β with a pro-inflammatory phenotype characterised by cytokine expression (e.g., interleukins (IL) 1β and 6 and tumour necrosis factor α (TNFα)) that may initially limit amyloidosis but likely becomes overzealous and neurotoxic [12,13,14].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [13]
In the citing paper
“For example, PS1-APP mice (a model of Alzheimer's Disease) showed an age-dependent reduction in receptors and enzymes involved in beta amyloid degradation, although still maintaining elevated levels of cytokine (Hickman et al, 2008).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Hickman et al, 2008
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Citations
Cites
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Macrophages and microglia in the nervous system
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Co-expression of multiple transgenes in mouse CNS: a comparison of strategies
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“…hypothesis, we developed a method to isolate fresh adult mouse microglia from the bigenic APPswe/PSEN1dE9 (PS1-APP) mice (Borchelt et al., 1997; Jankowsky et al., 2001), a robust mouse model of AD, and from their nontransgenic littermates at various ages and stages of AD-like pathology, and…”
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Items 501–600 of 1,003
Exercise-Induced Modulation of Neuroinflammation in Models of Alzheimer’s Disease
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Mortimer, P. M., McIntyre, S., & Thomas, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.733918 · Cited by 63
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“Recently, these fi ndings have been backed up by observations indicating that microglia may change from alternative to classical phenotype over time (Colton et al., 2006; Hickman et al., 2008; Jimenez et al., 2008; Lucin and Wyss-Coray, 2009), although probably there is a heterogeneous population.”
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BackgroundNanomaterials as Microglia Modulators in the Treatment of Central Nervous System Disorders
Battaglini, M., Marino, A., Montorsi, M., Carmignani, A., Ceccarelli, M. C., & Ciofani, G. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202304180 · Cited by 54
Zhao, Z., Liu, Y., Ruan, S., & Hu, Y. (2023) · International Journal of Nanomedicine · doi:10.2147/ijn.s444115 · Cited by 49
“92 Astrocyte is responsible for cell-to-cell communication and part of the nutrients that neurons require.”
BackgroundXu, L., Yao, Z., Wu, H., Wang, F., & Zhang, S. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.06.019 · Cited by 50
Acosta, S., Tajiri, N., Sanberg, P., Kaneko, Y., & Borlongan, C. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25629 · Cited by 49
“TBI as a risk factor for AD pathology may involve a dysfunctional immune clearance of APPþ and Ab by activated MHCIIþ cells and an aberrant overexpression of APP and Ab (Selkoe, 1997; Sheng et al., 2003; Hickman et al., 2008).”
BackgroundSoluble TREM2 and Inflammatory Proteins in Alzheimer’s Disease Cerebrospinal Fluid
Rauchmann, B., Sadlon, A., Perneczky, R., & Initiative, A. D. N. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-191120 · Cited by 50
c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases
Rehfeldt, S. C. H., Majolo, F., Goettert, M. I., & Laufer, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249677 · Cited by 47
“In vivo AD models corroborate this hypothesis, since it was found that microglia decrease the expression of their Aβbinding receptors and Aβ-degrading enzymes while maintaining the ability to produce proinflammatory cytokines [113].”
BackgroundCimino, P. J., Sokal, I., Leverenz, J., Fukui, Y., & Montine, T. J. (2009) · The American Journal of Pathology · doi:10.2353/ajpath.2009.090443 · Cited by 49
Cerebrospinal Fluid Cytokine Dynamics Differ Between Alzheimer Disease Patients and Elderly Controls
Llano, D. A., Li, J., Waring, J. F., Ellis, T. A., Devanarayan, V., Witte, D. G., & Lenz, R. A. (2011) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e31823b2728 · Cited by 49
Montgomery, S. L., Narrow, W. C., Mastrangelo, M. A., Olschowka, J. A., O'Banion, M. K., & Bowers, W. J. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.02.030 · Cited by 58
“This observation coincides with a significant increase in TNF-a transcript level at the same age, suggesting that the up-regulation of TNF-a compromises Ab-degrading pathways.(51) This report supports the possibility that unopposed TNF-RI signaling in neuronsmay lead to the down-regulation of enzymes involved in Ab de…”
ResultMa, Q., Zhu, C., Morselli, M., Su, T., Pelligrini, M., Lu, Z., Jones, M. R., Denver, P., Castro, D., Gu, X., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.558036 · Cited by 48
“Although numerous studies have demonstrated that activated microglia respond to phagocytosis of Aβ (74), however, after a prolonged period of activation, these activated microglia may decrease or lose their Aβ phagocytic capacity (75, 76).”
BackgroundQi, C., Liu, F., Zhang, W., Han, Y., Zhang, N., Liu, Q., & Li, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1004885 · Cited by 50
Chimeric antigen receptor macrophages target and resorb amyloid plaques
Kim, A. B., Xiao, Q., Yan, P., Pan, Q., Pandey, G., Grathwohl, S., Gonzales, E. R., Xu, I., Cho, Y., Haecker, H., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.175015 · Cited by 50
“…to control plaque load with AD progression may be attributed to the reduced expression of A β binding receptors and A β -degrading enzymes as plaque deposition increases with age, and this was shown to lead to decreased phagocytosis and degradation of amyloid material in APP/PS1 mice (50).”
BackgroundMicroglia Signatures: A Cause or Consequence of Microglia-Related Brain Disorders?
Mirarchi, A., Albi, E., & Arcuri, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252010951 · Cited by 52
“In diseases such as AD and PD, pathological microglia interact with pathological protein aggregates (amyloid-β , tau, and α -synuclein) [85,86], but often with reduced phagocytic efficacy, contributing to the accumulation of these aggregates.”
BackgroundGoñi, F., Prelli, F., Ji, Y., Scholtzova, H., Yang, J., Sun, Y., Liang, F., Kascsak, R., Kascsak, R. J., Mehta, P. D., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013391 · Cited by 48
Williams, C. J., & Dexter, D. T. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12608 · Cited by 48
Zheng, W., Li, Q., Zhao, C., Da, Y., Zhang, H., & Chen, Z. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00239 · Cited by 50
“However, the roles of microglia in AD may be a double-edged sword, which should be taken into account when contemplating microglial or anti-inflammatory therapy for AD (Hickman et al., 2008; Tang and Le, 2016).”
BackgroundPotential Role of Fluoride in the Etiopathogenesis of Alzheimer’s Disease
Goschorska, M., Baranowska‐Bosiacka, I., Gutowska, I., Metryka, E., Skórka-Majewicz, M., & Chlubek, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123965 · Cited by 48
“It has also been established that overproduction of IL-1, IL-6, and TNF-α stimulates the synthesis of Aβ [85] and IL-1 is associated with both the initiation and spread of neuroinflammation in AD [86].”
BackgroundPhagocytosis of Apoptotic Cells Is Specifically Upregulated in ApoE4 Expressing Microglia in vitro
Muth, C., Hartmann, A., Falla, D. S., Glatzel, M., & Krasemann, S. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00181 · Cited by 47
“…microglia from newborn mice: While N9 show some overlapping expression characteristics with adult microglia, primary microglia isolated from brains of newborn mice display an expression signature that is very different from microglia in the adult brain (Hickman et al., 2008; Butovsky et al., 2014).”
BackgroundMcFarland, K. N., & Chakrabarty, P. (2022) · Neurotherapeutics · doi:10.1007/s13311-021-01179-3 · Cited by 48
Ren, S., Breuillaud, L., Yao, W., Yin, T., Norris, K. A., Zehntner, S. P., & D’Adamio, L. (2021) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.016395 · Cited by 47
“Several data support the hypothesis that pathogenic TREM2 variants hamper the toxicAβ-clearing activities ofmicroglia (2, 3) and that elevated TNF-α levels cause increased Aβ production (18–21) and reduced microglial clearance of Aβ (22), yet we see no evidence of alteredAβmetabolism in youngTrem2 rats.”
BackgroundWeng, S.-T., Lai, Q., Wang, J., Zhuang, L., Cheng, L., Mo, Y., Liu, L., Zhao, Z., Zhang, Y., & Qiao, S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.899944 · Cited by 49
“After a series of in-depth studies, it was found that MSCs may play a therapeutic role through exosomes (Hu et al., 2015; Zhang et al., 2015; Zhu et al., 2017).”
BackgroundRedox regulation, protein S-nitrosylation, and synapse loss in Alzheimer’s and related dementias
Oh, C.-K., Nakamura, T., Zhang, X., & Lipton, S. A. (2024) · Neuron · doi:10.1016/j.neuron.2024.10.013 · Cited by 52
Akitake, Y., Nakatani, Y., Kamei, D., Hosokawa, M., Akatsu, H., Uematsu, S., Akira, S., Kudo, I., Hara, S., & Takahashi, M. (2013) · Journal of Neuroscience Research · doi:10.1002/jnr.23217 · Cited by 47
“…the disease progresses, with the persistent production of proinflammatory cytokines, the microglia lose their protective phenotype and their ability to counteract Ab deposition, and they ultimately become dysfunctional and unable to clear all of the Ab present in the system (Hickman et al., 2008).”
BackgroundSweepers in the CNS: Microglial Migration and Phagocytosis in the Alzheimer Disease Pathogenesis
Noda, M., & Suzumura, A. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/891087 · Cited by 52
“Microglia from old APP/PS1 mouse, but not from younger ones, show the reduction of SRA, CD36, RAGE, and the Aβ-degrading enzymes including insulysin, neprilysin, and MMP9 [121].”
BackgroundBellozi, P. M. Q., Lima, I. V. D. A., Doria, J. G., Vieira, É. L. M., Campos, A. C., Candelario‐Jalil, E., Reis, H. J., Teixeira, A. L., Ribeiro, F. M., & de Oliveira, A. C. P. (2016) · Scientific Reports · doi:10.1038/srep25226 · Cited by 47
Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer’s pathology
Zhang, Z., Takeda‐Uchimura, Y., Foyez, T., Ohtake‐Niimi, S., Narentuya, Akatsu, H., Nishitsuji, K., Michikawa, M., Wyss‐Coray, T., Kadomatsu, K., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1615036114 · Cited by 48
In Vivo Imaging of Microglia With Multiphoton Microscopy
Hierro‐Bujalance, C., Bacskai, B. J., & García-Alloza, M. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00218 · Cited by 50
de Dios, C., Bartolessis, I., Agujetas, V. R., Barbero‐Camps, E., Marı́, M., Morales, A., & Colell, A. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101283 · Cited by 49
Myhre, C. L., Thygesen, C., Villadsen, B., Vollerup, J., Ilkjær, L., Krohn, K. T., Grebing, M., Zhao, S., Khan, A. M., Dissing‐Olesen, L., et al. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00308 · Cited by 45
“While it is well-known that microglia are a major source of TNF in transgenic mouse models of AD (Hickman et al., 2008; Minogue et al., 2014; Babcock et al., 2015), there is less information about microglia as a significant local source of IGF-1.”
BackgroundStress and Alzheimer’s disease: A senescence link?
Lyons, C. E., & Bartolomucci, A. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.05.010 · Cited by 49
Cecarini, V., Bonfili, L., Gogoi, O., Lawrence, S., Venanzi, F. M., Azevedo, V., Mancha-Agresti, P. D. C., Drumond, M. M., Rossi, G., Berardi, S., et al. (2020) · Aging · doi:10.18632/aging.103900 · Cited by 49
“In addition, since Aβ is a direct source of oxidative stress and that its deposition is linked to microglia activation and sustained pro-inflammatory signaling, reduction of its levels further contributes to counteract the two detrimental processes [48, 50, 55, 56].”
BackgroundEmerging potential of cannabidiol in reversing proteinopathies
Dash, R., Ali, M. C., Jahan, I., Munni, Y. A., Mitra, S., Hannan, M. A., Timalsina, B., Oktaviani, D. F., Choi, H. J., & Moon, I. S. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101209 · Cited by 50
“In AD, aggregated Aβ peptide (β-amyloid) is recognized as a typical hallmark (Hickman et al., 2008; Streit, 2004), which triggers the imbalance of different phosphatases and protein kinases that maintains several cellular signals.”
BackgroundGlial Purinergic Signaling in Neurodegeneration
Pietrowski, M. J., Gabr, A. A., Kozlov, S. O., Blum, D. L., Halle, A., & Carvalho, K. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.654850 · Cited by 49
Neurodegeneration and the neuroimmune system
El Khoury, J. (2010) · Nature Medicine · doi:10.1038/nm1210-1369 · Cited by 46
Optical Nanosensor for Intracellular and Intracranial Detection of Amyloid-Beta
Antman‐Passig, M., Wong, E., Frost, G. R., Cupo, C., Shah, J., Agustinus, A. S., Chen, Z., Mancinelli, C. D., Kamel, M., Li, T., et al. (2022) · ACS Nano · doi:10.1021/acsnano.2c00054 · Cited by 45
Microglia-Mediated Neurovascular Unit Dysfunction in Alzheimer’s Disease
Huang, W., Xia, Q., Zheng, F., Zhao, X. L., Ge, F., Xiao, J., Liu, Z., Shen, Y., Ye, K., Wang, D., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221064 · Cited by 47
“Though early recruitment of microglia may be neuroprotective by A clearance, microglial engulfment, and degradation of A is suppressed and proinflammatory cytokines are increased as disease progresses [15].”
BackgroundIKKβ Deficiency in Myeloid Cells Ameliorates Alzheimer's Disease-Related Symptoms and Pathology
Liu, Y., Liu, X., Hao, W., Decker, Y., Schomburg, R., Fülöp, L., Pasparakis, M., Menger, M. D., & Fassbender, K. C. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1348-14.2014 · Cited by 46
“7E; one-way ANOVA, p 0.05), a finding consistent with the observations of El Khoury’s group (Hickman et al., 2008).”
ResultInfluentialCSF beta‐amyloid levels are altered in narcolepsy: a link with the inflammatory hypothesis?
Liguori, C., Placidi, F., Albanese, M., Nuccetelli, M., Izzi, F., Marciani, M. G., Mercuri, N. B., Bernardini, S., & Romigi, A. (2014) · Journal of Sleep Research · doi:10.1111/jsr.12130 · Cited by 46
“Indeed, the inflammatory pathways of the immune system represent targets for modulating beta amyloid generation and accumulation (Hickman et al., 2008).”
BackgroundCalcium Signaling Deficits in Glia and Autophagic Pathways Contributing to Neurodegenerative Disease
Mustaly-Kalimi, S., Littlefield, A. M., & Stutzmann, G. E. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7266 · Cited by 47
“Although microglia activity could be benefi-cial in initially clearing A b oligomers in earlier stages of AD, the increasing A b aggregation generates excess release of proinflammatory cytokines and inflammatory factors, which can contribute to neurodegeneration (71, 83, 91).”
Secretomics to Discover Regulators in Diseases
Song, P., Kwon, Y., Joo, J., Kim, D.-G., & Yoon, J. H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20163893 · Cited by 48
Azam, S., Haque, M. E., Kim, I., & Choi, D. (2021) · Cells · doi:10.3390/cells10010150 · Cited by 46
“Therefore, microglia approach the neuroinflammatory threshold by producing peripheral inflammatory cytokines such as TNF-α and IL-1β [33,34].”
BackgroundInfluentialImmunomodulatory Function of κ-Carrageenan Oligosaccharides Acting on LPS-Activated Microglial Cells
Yao, Z., Xu, L., & Wu, H. (2013) · Neurochemical Research · doi:10.1007/s11064-013-1228-4 · Cited by 46
Blume, T., Focke, C., Peters, F., Deußing, M., Albert, N. L., Lindner, S., Gildehaus, F., von Ungern‐Sternberg, B., Ozmen, L., Baumann, K., et al. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1347-6 · Cited by 45
Ren, D., Fu, Y., Wang, L., Liu, J., Zhong, X., Yuan, J., Jiang, C., Wang, H., & Li, Z. (2021) · Phytomedicine · doi:10.1016/j.phymed.2021.153627 · Cited by 45
Litwiniuk, A., Baranowska-Bik, A., Domańska, A., Kalisz, M., & Bik, W. (2021) · Pharmaceuticals · doi:10.3390/ph14121221 · Cited by 46
“In detail, abnormal microglia-specific NLRP3 activation induces microglia Aβ phagocytic dysfunction, peripheral nerve cell damage, and other severe pathological processes, including the promotion of Aβ plaque formation and accumulation [59,60].”
BackgroundIshihara, Y., Takemoto, T., Ishida, A., & Yamazaki, T. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/343706 · Cited by 45
TREM2 analysis and increased risk of Alzheimer's disease
Finelli, D., Rollinson, S. J., Harris, J., Jones, M. S., Richardson, A. M. T., Gerhard, A., Snowden, J. S., Mann, D. M. A., & Pickering-Brown, S. M. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.08.001 · Cited by 45
“Studies in APP transgenic mice have revealed that pro-inflammatory cytokines such as tumor necrosis factor and interferon-gare linked toenhanceddepositionand reducedclearance of beta-amyloid peptides (Hickman et al., 2008; Yamamoto et al., 2007).”
BackgroundInhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach
Veerappan, K., Natarajan, S., Ethiraj, P., Vetrivel, U., & Samuel, S. (2016) · Pharmaceutical Biology · doi:10.1080/13880209.2016.1241809 · Cited by 45
“The burgeoning number of research on inflammation and AD has shown that the pro-inflammatory environment negatively affects the ability of microglial cells to involve in phagocytosis and subsequent retention of Ab oligomers within the cells (Fiala et al. 2005; Zelcer et al. 2007; Hickman et al. 2008; Yamamoto et al. 2…”
BackgroundCellular Senescence, Neurological Function, and Redox State
Maciel-Barón, L. Á., Moreno-Blas, D., Morales-Rosales, S. L., González‐Puertos, V. Y., López‐Díazguerrero, N. E., Torres, C. A., Castro‐Obregón, S., & Königsberg, M. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7112 · Cited by 47
“Aged microglia change their surface antigen pattern by upregulating MHCII, CD11b, CD11c, and CD68, as well as the pattern recognition receptors, Toll-like receptor 4 (TLR4), CD14, and scavenger receptors (73, 97, 178), all of them related to the activated microglial phenotype (124).”
CD36 gene polymorphism is associated with Alzheimer's disease
Šerý, O., Janoutová, J., Ewerlingová, L., Hálová, A., Lochman, J., Janout, V., Khan, N. A., & Balcar, V. J. (2017) · Biochimie · doi:10.1016/j.biochi.2017.01.009 · Cited by 44
Function of Glia in Aging and the Brain Diseases
Vallés, S. L., Iradi, A., Aldasoro, M., Vila, J. M., Aldasoro, C., de la Torre, J., Campos-Campos, J., & Jorda, A. (2019) · International Journal of Medical Sciences · doi:10.7150/ijms.37769 · Cited by 45
“This idea is supported by in vitro studies in which treatment of microglia with TNF-α resulted in a reduction of the expression of SRA and CD36, and uptake of Aβ (14).”
ResultRole of neurotoxicants in the pathogenesis of Alzheimer’s disease: a mechanistic insight
Nisa, F. Y., Rahman, M. A., Hossen, M. A., Khan, M. F., Khan, M. A. N., Majid, M., Sultana, F., & Haque, M. A. (2021) · Annals of Medicine · doi:10.1080/07853890.2021.1966088 · Cited by 44
Souza, L. C., Jessé, C. R., Fabbro, L. D., de Gomes, M. G., Goes, A. T. R., Filho, C. B., Luchese, C., Pereira, A. A. M., & Boeira, S. P. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.05.024 · Cited by 47
Kim, D. H., Lee, D., Lim, H., Choi, S. J., Oh, W., Yang, Y. S., Chang, J. H., & Jeon, H. B. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.09.012 · Cited by 44
Thygesen, C., Ilkjær, L., Kempf, S. J., Hemdrup, A. L., von Linstow, C. U., Babcock, A. A., Darvesh, S., Larsen, M. R., & Finsen, B. R. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00397 · Cited by 44
Inhibition of formyl peptide receptors improves the outcome in a mouse model of Alzheimer disease
Schröder, N., Schaffrath, A., Welter, J. A., Putzka, T., Griep, A., Ziegler, P., Brandt, E., Samer, S., Heneka, M. T., Kaddatz, H., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01816-2 · Cited by 43
Jiang, T., Wan, Y., Zhang, Y.-D., Zhou, J.-S., Gao, Q., Zhu, X.-C., Shi, J.-Q., Lu, H., Tan, L., & Yu, J.-T. (2017) · Molecular Neurobiology · doi:10.1007/s12035-016-9704-x · Cited by 46
Chang, K.-W., Zong, H.-F., Ma, K., Zhai, W.-Y., Yang, W., Hu, X., Xu, J., Chen, X., Ji, S., & Qian, Y. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.09.005 · Cited by 44
“Both astrocytes and microglia can internalize and degrade Aβ (Guénette, 2003; Hickman et al., 2008).”
BackgroundLilrB3 is a putative cell surface receptor of APOE4
Zhou, J., Wang, Y., Huang, G., Yang, M., Zhu, Y., Jin, C., Jing, D., Ji, K., & Shi, Y. (2023) · Cell Research · doi:10.1038/s41422-022-00759-y · Cited by 44
Monoclonal Antibody Therapy in Alzheimer’s Disease
Neațu, M., Covaliu, A., Ioniță, I., Jugurt, A., Davidescu, E. I., & Popescu, B. O. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics16010060 · Cited by 46
“Furthermore, an enduring proinflammatory state diminishes the capacity to clear A β , consequently exacerbating the progression of AD [60].”
BackgroundCankar, N., Beschörner, N., Tsopanidou, A., Qvist, F. L., Colaço, A. R., Andersen, M., Kjærby, C., Delle, C., Lambert, M., Mundt, F., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114977 · Cited by 45
“44,45 Taking the results together, we find that microglial cells were activated 24 h after sleep deprivation in WT but not in young APP/PS1 mice.”
Puli, L., Pomeshchik, Y., Olas, K., Malm, T., Koıstınaho, J., & Tanila, H. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-105 · Cited by 48
“This profile of immunomodulation works against the profile associated with aging [6] and may confer neuroprotection in the AD brain.”
BackgroundReda, H. M., Zaitone, S. A., & Moustafa, Y. M. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.12.035 · Cited by 44
Metadata
- Authors
- Hickman, S. E., Allison, E. K., & El Khoury, J.
- Affiliations
- Harvard University (US)
- ORCID
- Hickman, Suzanne E.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-08-13
- Volume
- 28
- Issue
- 33
- Pages
- 8354-8360
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2597474
- OpenAlex
- W2018708829
- Cited by
- 1,329
- References
- 28
- Citations by year
- 2026: 49 · 2025: 85 · 2024: 85 · 2023: 96 · 2022: 125 · 2021: 98 · 2020: 113 · 2019: 91 · 2018: 78 · 2017: 63 · 2016: 67 · 2015: 73 · 2014: 64 · 2013: 49 · 2012: 65
- FWCI
- 27.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dana Foundation
- National Institute of Neurological Disorders and Stroke (R01NS059005)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- Alzheimer's disease, microglia, amyloid-beta clearance, aging, scavenger receptor A, CD36, RAGE, neprilysin, MMP-9, inflammatory cytokines, TNF-α, IL-1β, neuroinflammation, anti-inflammatory therapy, neurodegeneration
- MeSH terms
- Aging, Alzheimer Disease, Animals, Mice, Transgenic, Signal Transduction, Amyloid beta-Peptides, Microglia, Mice
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