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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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“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
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Self-citationA review on advances of treatment modalities for Alzheimer's disease
Thoe, E. S., Fauzi, A., Tang, Y.-Q., Chamyuang, S., & Chia, A. Y. Y. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119129 · Cited by 234
Dysfunctional Mitochondria and Mitophagy as Drivers of Alzheimer’s Disease Pathogenesis
Chakravorty, A., Jetto, C. T., & Manjithaya, R. R. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00311 · Cited by 225
“…AD progression, microglia exhibit increased levels of pro-inflammatory cytokines such as tumor necrosis factorα (TNF-α) and interleukin-6 (IL6) along with decreased production of anti-inflammatory cytokine IL-10 due to their persistent activated state (Hickman et al., 2008; Lautrup et al., 2019).”
BackgroundThe role of the immune system in Alzheimer disease: Etiology and treatment
Jevtic, S. D., Sengar, A. S., Salter, M. W., & McLaurin, J. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.005 · Cited by 224
Microglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan
Tay, T. L., Béchade, C., D’Andrea, I., St‐Pierre, M., Henry, M. S., Roumier, A., & Tremblay, M. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00421 · Cited by 217
“, insulysin, neprilysin, MMP9) was detected ex vivo in microglia from APP/PS1 mice (Hickman et al., 2008).”
BackgroundRole 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 224
Frenkel, D., Wilkinson, K., Zhao, L., Hickman, S. E., Means, T. K., Puckett, L., Farfara, D., Kingery, N. D., Weiner, H. L., & El Khoury, J. (2013) · Nature Communications · doi:10.1038/ncomms3030 · Cited by 214
“Unfortunately, with aging and progression of Alzheimer’s disease, innate immune cells of the brain appear to become dysfunctional and their ability to clear amyloid becomes significantly reduced 4 .”
BackgroundInfluentialSelf-citationTREM2, microglia, and Alzheimer’s disease.
Qin, Q., Teng, Z., Liu, C., Li, Q., Yin, Y., & Tang, Y. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111438 · Cited by 219
Streit, W. J., & Xue, Q.-S. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9163-5 · Cited by 205
Old Maids: Aging and Its Impact on Microglia Function
Koellhoffer, E. C., McCullough, L. D., & Ritzel, R. M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040769 · Cited by 213
“In the setting of AD pathology, microglia PS1-APP mice were found to have elevated RNA expression of IL1B and TNFA at 8-months of age with further elevation in expression by 14-months [149].”
BackgroundInfluentialFluorescent Diagnostic Probes in Neurodegenerative Diseases
Zhou, J., Jangili, P., Son, S., Ji, M. S., Won, M., & Kim, J. S. (2020) · Advanced Materials · doi:10.1002/adma.202001945 · Cited by 204
Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease
Gamba, P., Testa, G., Gargiulo, S., Staurenghi, E., Poli, G., & Leonarduzzi, G. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00119 · Cited by 180
“, 2004; Colton and Wilcock, 2010) but, in later stages of AD, the increased inflammatory molecule release makes the microglia phagocytically inactive leading to neuronal death (Hickman et al., 2008; Krabbe et al., 2013).”
BackgroundXiong, H., Callaghan, D., Jones, A., Bai, J., Rasquinha, I., Smith, C., Pei, K., Walker, D. G., Lue, L., Stanimirovic, D. B., et al. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.5103-08.2009 · Cited by 214
“Previous studies described secretion of proinflammatory cytokines, such as IL-1 and TNF- , from A -treated microglia (Walker et al., 2001; Lue and Walker 2002; Hickman et al., 2008).”
BackgroundThe role of inflammasome in Alzheimer's disease
Liu, L., & Chan, C. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2013.12.007 · Cited by 196
“The lower clearance is due to a significant decrease in he expression of A binding scavenger receptors and A degrading nzymes in microglia (Hickman et al., 2008; Johnston et al., 2011). herefore, the exact function of microglia in AD, whether it is benficial or detrimental, may depend on the…”
BackgroundInfluentialTumor necrosis factor α Inhibition for Alzheimer’s Disease
Chang, R., Yee, K.-L., & Sumbria, R. K. (2017) · Journal of Central Nervous System Disease · doi:10.1177/1179573517709278 · Cited by 195
Ahmad, M. H., Fatima, M., & Mondal, A. C. (2018) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2018.10.034 · Cited by 201
Neuroinflammation and neurogenesis in Alzheimer's disease and potential therapeutic approaches
Sung, P.-S., Lin, P.-Y., Liu, C.-H., Su, H.-C., & Tsai, K.-J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21030701 · Cited by 193
“Chronic activated microglia due to Aβ produces proinflammatory mediators, which lead to decreased phagocytosis ability and prolong neuroinflammation [159].”
BackgroundConnecting aging biology and inflammation in the omics era
Walker, K. A., Basisty, N., Wilson, D. M., & Ferrucci, L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158448 · Cited by 189
Jian, M., Kwan, J., Bunting, M., Ng, R. C.-L., & Chan, K. H. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1492-6 · Cited by 191
“They respond rapidly to pathological triggers, such as neuronal death or protein aggregates, and remove them via phagocytosis and degradation [14].”
Backgroundβ-amyloid, microglia, and the inflammasome in Alzheimer’s disease
Gold, M., & El Khoury, J. (2015) · Seminars in Immunopathology · doi:10.1007/s00281-015-0518-0 · Cited by 187
Pathological role of hypoxia in Alzheimer's disease
Zhang, X., & Le, W. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.07.033 · Cited by 190
“Under hypoxic conditions, endogenous BACE1, βCTF, and Aβ in SH-SY5Y cells are all markedly increased.”
BackgroundInfluentialTargeting microglia for the treatment of Alzheimer’s Disease
Wes, P. D., Sayed, F. A., Bard, F., & Gan, L. (2016) · Glia · doi:10.1002/glia.22988 · Cited by 185
“While microglia’s response to injury is typically beneficial, it can go awry, particularly in cases of chronic injury and long-term inflammation, such as in AD (Hickman et al., 2008; Lucin and Wyss-Coray, 2009).”
BackgroundMicroglial Scavenger Receptors and Their Roles in the Pathogenesis of Alzheimer's Disease
Wilkinson, K., & Khoury, J. B. E. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/489456 · Cited by 197
“This inflammatory environment ultimately becomes toxic to the surrounding neurons, resulting in neuronal degeneration and disease progression [16].”
BackgroundFu, H., Liu, B., Frost, J. L., Hong, S., Jin, M., Ostaszewski, B., Shankar, G. M., Costantino, I. M., Carroll, M. C., Mayadas, T. N., et al. (2012) · Glia · doi:10.1002/glia.22331 · Cited by 180
“The cells were cultured as described and have been shown previously to take up Aβ (Hickman et al. 2008).”
BackgroundInfluentialAmyloid fibrils are the molecular trigger of inflammation in Parkinson's disease
Gustot, A., Gallea, J. I., Sarroukh, R., Celej, M. S., Ruysschaert, J., & Raussens, V. (2015) · Biochemical Journal · doi:10.1042/bj20150617 · Cited by 190
Reactive glia show increased immunoproteasome activity in Alzheimer’s disease
Orre, M., Kamphuis, W., Dooves, S., Kooijman, L., Chan, E. T., Kirk, C. J., Dimayuga Smith, V., Koot, S., Mamber, C., Jansen, A. H., et al. (2013) · Brain · doi:10.1093/brain/awt083 · Cited by 180
“Sustained immune signalling has previously been shown to lead to reduced levels of amyloid-b recognition receptors and of amyloidb degrading enzymes in microglia from aged Alzheimer’s disease mice (Hickman et al., 2008), as well as a reduction of general cognitive functions (Corona et al., 2011).”
BackgroundThe endocannabinoid system as a target for the treatment of neurodegenerative disease
Scotter, E. L., Abood, M. E., & Glass, M. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00735.x · Cited by 188
“…proposes that misfolded b-amyloid is both injurious to neurons and also invokes a microglial response which, while perhaps evolved to phagocytically clear plaques, is itself neurotoxic (Haga et al., 1989; Itagaki et al., 1989; Hardy and Higgins, 1992; Streit et al., 2005; Hickman et al., 2008).”
Current Concepts of Neurodegenerative Mechanisms in Alzheimer’s Disease
Magalingam, K. B., Radhakrishnan, A., Ping, N. S., & Haleagrahara, N. (2018) · BioMed Research International · doi:10.1155/2018/3740461 · Cited by 178
Kahn, M. S., Kranjac, D., Alonzo, C. A., Haase, J. H., Cedillos, R. O., McLinden, K. A., Boehm, G. W., & Chumley, M. J. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.01.010 · Cited by 177
Toll-Like Receptors in Alzheimer's Disease
Landreth, G. E., & Reed-Geaghan, E. G. (2009) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-00549-7_8 · Cited by 180
“It is hypothesized that while microglia clear Aβ in early stages of AD, as the disease progresses, genes involved in Aβ clearance are down-regulated due to increased proinflammatory gene expression, contributing to Aβ accumulation (Hickman et al. 2008).”
BackgroundMicroglia Activation and Anti-inflammatory Regulation in Alzheimer’s Disease
Lue, L., Kuo, Y., Beach, T. G., & Walker, D. G. (2010) · Molecular Neurobiology · doi:10.1007/s12035-010-8106-8 · Cited by 173
Graphene quantum dots conjugated neuroprotective peptide improve learning and memory capability
Xiao, S., Zhou, D., Luan, P., Gu, B., Feng, L., Fan, S., Liao, W., Fang, W., Yang, L., Tao, E., et al. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.08.021 · Cited by 169
Young microglia restore amyloid plaque clearance of aged microglia
Daria, A., Colombo, A., Llovera, G., Hampel, H., Willem, M., Liesz, A., Haass, C., & Tahirovic, S. (2017) · The EMBO Journal · doi:10.15252/embj.201694591 · Cited by 174
“…and this may compromise not only phagocytic, but also other physiological functions, including chemokine, cytokine, and growth factor secretion (Lue et al , 2001; Hanisch & Kettenmann, 2007; Hickman et al , 2008; Lai & McLaurin, 2012; Solito & Sastre, 2012; Derecki et al , 2014; Orre et al , 2014).”
Activation of the CB2 receptor system reverses amyloid-induced memory deficiency
Wu, J., Bie, B., Yang, H., Xu, J. J., Brown, D. L., & Naguib, M. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.06.011 · Cited by 180
“Microglia play an important role in promoting the clearance and phagocytosis of A (Rogers et al., e o a A p l t d 1 m m c A a A A D C A a C R 2002; Streit, 2004; Yan et al., 1996, 2006) and there is an inverse relationship between cytokine production and A clearance (Hickman et al., 2008).”
Mechanisms of microglia accumulation in Alzheimer’s disease: therapeutic implications
Khoury, J. E., & Luster, A. D. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.08.004 · Cited by 171
Self-citationImaging Microglial Activation During Neuroinflammation and Alzheimer’s Disease
Venneti, S., Wiley, C. A., & Kofler, J. (2008) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-008-9142-2 · Cited by 172
“Proinflammatory cytokines such as TNF-α have been shown to induce a downregulation of Aβ receptors, which may start a vicious cycle, by leading to a further compromise in the phagocytic capacity of microglia (Hickman et al. 2008).”
BackgroundInfluentialReduction of β-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease
Paris, D., Ganey, N. J., Laporte, V., Patel, N. S., Beaulieu‐Abdelahad, D., Bachmeier, C. J., March, A., Ait‐Ghezala, G., & MULLAN, M. J. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-17 · Cited by 169
“For instance, celastrol may also lower brain Ab levels by opposing inflammation, cytokines production and CD40 ligand expression, all of which are known to modulate the accumulation of Ab in the brain [38-40].”
BackgroundA Critical Role of Autophagy in Regulating Microglia Polarization in Neurodegeneration
Jin, M.-M., Wang, F., Qi, D., Liu, W.-W., Gu, C., Mao, C.-J., Yang, Y.-P., Zhao, Z., Hu, L.-F., & Liu, C.-F. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00378 · Cited by 180
“The extracellular triggers were extensively reported, such as betaamyloid and LPS (Qin et al., 2007; Hickman et al., 2008).”
BackgroundSanchez‐Ramos, J., Song, S., Sava, V. M., Catlow, B. J., Lin, X., Mori, T., Cao, C., & Arendash, G. W. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.05.071 · Cited by 165
“The ability of G-CSF to enhance mobilization/recruitment of “new” bone marrow–derived microglia may be particularly important in view of a recent study showing that, as APP PS1 mice age, their microglia become dysfunctional by exhibiting significantly reduced expression of A -binding receptors and A -degrading enzymes…”
Tai, L. M., Ghura, S., Koster, K. P., Liakaite, V., Maienschein‐Cline, M., Kanabar, P., Collins, N., Ben‐Aissa, M., Lei, A. Z., Bahroos, N., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13072 · Cited by 165
“Indeed, although Ab phagocytosis will be beneficial for AD, an associated chronic pro-inflammatory response and decreased anti-inflammatory/repair response may lower the expression of phagocytic receptors (Hickman et al. 2008), induce neuronal damage, and prevent neuronal recovery.”
Yang, H., Xie, Z., Wei, L. F., Yang, H. N., Yang, S. N., Zhu, Z., Wang, P., Zhao, C., & Bi, J. Z. (2013) · Stem Cell Research & Therapy · doi:10.1186/scrt227 · Cited by 167
“mouse model [53].”
Mitochondrial Oxidative Stress and “Mito-Inflammation”: Actors in the Diseases
Patergnani, S., Bouhamida, E., Leo, S., Pinton, P., & Rimessi, A. (2021) · Biomedicines · doi:10.3390/biomedicines9020216 · Cited by 178
Martin, E., Boucher, C., Fontaine, B., & Delarasse, C. (2017) · Aging Cell · doi:10.1111/acel.12522 · Cited by 156
“We found consistent results with those determined at the mRNA level for increased expression of IL-1b, TNF-a, CCL-3, and iNOS (Hickman et al., 2008; Jimenez et al., 2008; Minogue et al., 2014; Babcock et al., 2015), but we observed differences for IL-4, IL-10, and CD36 previously shown to be…”
BackgroundResultInfluentialMicroglia Demonstrate Age-Dependent Interaction with Amyloid-β Fibrils
Floden, A. M., & Combs, C. K. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101014 · Cited by 166
“Indeed, an age- and disease-dependent change in microglial phenotype including expression of A interacting proteins has been reported from microglia isolated from an A PP/PS1 mouse model of disease [61].”
Clearance of Amyloid-β Peptides By Microglia and Macrophages: the Issue of What, When and Where
Lai, A. Y., & McLaurin, J. (2012) · Future Neurology · doi:10.2217/fnl.12.6 · Cited by 166
Pathological correlations between traumatic brain injury and chronic neurodegenerative diseases
Cruz-Haces, M., TANG, J. C. Y., Acosta, G., Fernandez, J., & Shi, R. (2017) · Translational Neurodegeneration · doi:10.1186/s40035-017-0088-2 · Cited by 166
“In other words, microglia recruitment promotes Aβ clearance and is neuroprotective in early stages of AD, but as the disease progresses, inflammatory cytokines downregulate Aβ clearance genes, and promote Aβ accumulation, contributing to neurodegeneration [99].”
BackgroundSoluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration
Sanchez-Mejias, E., Navarro, V., Jimenez, S., Sanchez-Mico, M., Sanchez-Varo, R., Nuñez-Diaz, C., Trujillo-Estrada, L., Davila, J. C., Vizuete, M., Gutierrez, A., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1630-5 · Cited by 175
“Although the inflammatory response could contribute to Abeta phagocytosis [11, 20], it has been associated with a neurotoxic detrimental effect mediated by the release of proinflammatory cytokines/ chemokines and neurotoxins [16, 17, 19].”
BackgroundNeural cell cycle dysregulation and central nervous system diseases
Wang, W., Bu, B., Xie, M., Zhang, M., Yu, Z., & Tao, D. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.01.007 · Cited by 164
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 174
Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models
Johansson, J. U., Woodling, N. S., Wang, Q., Panchal, M., Liang, X., Trueba-Saiz, A., Brown, H. D., Mhatre, S. D., Loui, T., & Andreasson, K. I. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77487 · Cited by 161
“Moreover, prolonged exposure to proinflammatory cytokines or accumulating A β 42 peptides cause microglia to lose their normal abilities to clear toxic proteins and control inflammation (13, 14), a detrimental phenotype in the context of age-associated A β 42 accumulation.”
Scavenger Receptor-A (CD204): A Two-Edged Sword in Health and Disease
Kelley, J., Ozment, T. R., Li, C., Schweitzer, J. B., & Williams, D. L. (2014) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.2014010267 · Cited by 160
Grimm, M. O. W., Mett, J., Stahlmann, C. P., Haupenthal, V. J., Zimmer, V. C., & Hartmann, T. (2013) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2013.00098 · Cited by 170
“In the central nervous system NEP is mainly expressed by neurons (Matsas et al., 1986), but also by activated astrocytes and microglia (Fisk et al., 2007; Hickman et al., 2008).”
BackgroundCai, M., Lee, J., & Yang, E. J. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1665-3 · Cited by 163
Haure-Mirande, J.-V., Audrain, M., Ehrlich, M. E., & Gandy, S. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00552-w · Cited by 159
“Despite their roles as “first responder” cells, the microglia arriving at the sites of AD-related proteinopathies can soon see their clean-up capacities outstripped, which, associated with the production of proinflammatory cytokines, can contribute to disease progression and neurodegeneration [9].”
BackgroundRole of TGFβ signaling in the pathogenesis of Alzheimer’s disease
von Bernhardi, R., Cornejo, F., Parada, G. E., & Eugenín, J. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00426 · Cited by 149
“…effects depend, at least partly, on the upregulation of Toll-like receptors (TLRs), increased expression of the TLR4 co-receptor CD14 (Letiembre et al., 2007), changes in TLR4 signaling, and changes on the expression profile of scavenger receptors (SRs; Yamamoto et al., 2002; Hickman et al., 2008).”
BackgroundBao, J., Zheng, L., Zhang, Q., Li, X., Zhang, X., Li, Z., Bai, X., Zhang, Z., Huo, W., Zhao, X., et al. (2016) · Protein & Cell · doi:10.1007/s13238-016-0269-2 · Cited by 159
“…cannot be fully eliminated or even remain stable albeit by surrounding coverage of activated microglia (Bolmont et al., 2008; Wegiel et al., 2001), which may be explained in part by the dysfunction of lysosomes in the presence of Aβ stimulation (Hickman et al., 2008; Majumdar et al., 2007).”
Alzheimer Disease and Its Growing Epidemic
Hickman, R. A., Faustin, A., & Wısnıewskı, T. (2016) · Neurologic Clinics · doi:10.1016/j.ncl.2016.06.009 · Cited by 163
“However, with aging, the efficacy of microglial breakdown is likely to be lost, and may even accentuate the accumulation, thereby causing a gradual shift toward accumulation of amyloid in the dynamic Ab turnover.(99)”
BackgroundBoyd, R. J., Avramopoulos, D., Jantzie, L. L., & McCallion, A. S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02584-x · Cited by 168
“Paradoxically, clearance of Aβ by microglia may exacerbate Aβ pathology: as chronically activated microglia release pro-inflammatory mediators and become even more pro-inflammatory, their capacity for clearing Aβ diminishes [32, 34] (Fig.”
BackgroundMicroglial amyloid beta clearance is driven by PIEZO1 channels
Jäntti, H., Sitnikova, V., Ishchenko, Y., Shakirzyanova, A., Giudice, L., Ugidos, I. F., Gómez‐Budia, M., Korvenlaita, N., Ohtonen, S., Belaya, I., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02486-y · Cited by 164
“The inability of microglia to clear accumulating toxic Aβ together with their proinflammatory functions are thought to be a significant contributor to LOAD pathology [5, 6].”
BackgroundRole of Endogenous Lipopolysaccharides in Neurological Disorders
Kalyan, M., Hediyal, T. A., Sonali, S., Vichitra, C., Sunanda, T., Praveenraj, S. S., Ray, B., Gorantla, V. R., Rungratanawanich, W., Mahalakshmi, A. M., et al. (2022) · Cells · doi:10.3390/cells11244038 · Cited by 172
“Other scientists also showed microglial hyperactivation and apoptosis of the hippocampal neurons in LPS-exposed mice [61,62].”
BackgroundRetinal pathological features and proteome signatures of Alzheimer’s disease
Koronyo, Y., Rentsendorj, A., Mirzaei, N., Regis, G. C., Sheyn, J., Shi, H., Barrón, E., Cook‐Wiens, G., Rodriguez, A., Medeiros, R., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02548-2 · Cited by 162
Neuroinflammation, gut microbiome, and Alzheimer's disease
Lin, L., Zheng, L. J., & Zhang, L. J. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0983-2 · Cited by 147
Koronyo, Y., Salumbides, B. C., Sheyn, J., Pelissier, L., Li, S., Ljubimov, V., Moyseyev, M., Daley, D., Fuchs, D.-T., Pham, M., et al. (2015) · Brain · doi:10.1093/brain/awv150 · Cited by 153
“Representative images show that increased fibrillar amyloid-b1–42 uptake following GA treatment was coupled with increased expression of the class B scavenger receptor CD36 (Fig.”
BackgroundInfluential
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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