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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]
Experimental — accuracy not yet measured
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In the citing paper
“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]
The cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
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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]
The cited source says what the claim attributes to it.
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).”
The 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 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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BackgroundActivation of microglial cells by β-amyloid protein and interferon-γ
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“To investigate this 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…”
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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…”
Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils
Khoury, J. E., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C., & Loike, J. D. (1996) · Nature · doi:10.1038/382716a0 · Cited by 727 · cited 2×
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BackgroundMethodSelf-citation
Cited by
Sorted by citations
Items 301–400 of 1,003
Microglia in Alzheimer’s disease: A target for immunotherapy
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Brain Derived Exosomes Are a Double-Edged Sword in Alzheimer’s Disease
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“Frontiers in Molecular Neuroscience | www.frontiersin.org 3 May 2020 | Volume 13 | Article 79 Frontiers in Molecular Neuroscience | www.frontiersin.org 4 May 2020 | Volume 13 | Article 79 FIGURE 2 | Continued to escape astrocyte signaling (Bolmont et al., 2008; Hickman et al., 2008).”
BackgroundNeuroinflammation: A Modifiable Pathway Linking Obesity, Alzheimer's disease, and Depression
Ly, M. J., Yu, G. Z., Mian, A., Cramer, A., Meysami, S., Merrill, D. A., Samara, A., Eisenstein, S. A., Hershey, T. G., Babulal, G. M., et al. (2023) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2023.06.001 · Cited by 114
“…become induced into the M1 subtype, 65 which have decreased phagocytic activity, diminished expression of beta-amyloid phagocytic receptors, resulting in impaired beta-amyloid clearance, 66 and contribute to oxidative stress through increased expression of inducible nitric oxide synthase (iNOS).”
BackgroundPrakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.029 · Cited by 104
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“Indeed, extensive microglial recruitment to plaques in human AD is accompanied by very little, if any, Ab phagocytosis [5,6], and occurs with increased production of proinflammatory cytokines that associate with cognitive decline [7].”
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BackgroundRole of Prostaglandins in Neuroinflammatory and Neurodegenerative Diseases
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Glial connexin expression and function in the context of Alzheimer's disease
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“…in vitro , they are inef fi cient to clear A β plaques in vivo , suggesting that the pathways involved in A β clearance are altered in AD [66, 69] Also, as central actors in neuroin fl ammation, microglial cells contribute to the in fl ammatory state observed in AD in which increased levels of…”
BackgroundPhosphodiesterase III inhibitor promotes drainage of cerebrovascular β‐amyloid
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“Taking into consideration that the inflammatory environment induced by Aβ-accumulation skews microglia to an inflammatory phenotype impairing its phagocytic capacity [33, 34] thus leading to the AD progression and that MpHE induced the phagocytic activity of neonatal microglia in primary cultures (Fig.”
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“The right hemispheres of animals in cohort 2 were processed to isolate CNS single-cell suspensions from the CCL2-and GFP-injected mouse brains as described NM_013650 S100A8 S100 calcium-binding protein A8 (calgranulin A) 3.1↑ P < 0.03 Calcium-binding protein involved in innate immune response [41] NM_009114 S100A9 S10…”
MethodInfluentialNeuroinflammation, Its Role in Alzheimer's Disease and Therapeutic Strategies
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“Recent studies suggest that high cytokine levels in the cerebrospinal fluid (CSF) reduce the capacity of Aβ uptake in the microglia (20).”
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“Excess production of proinflammatory cytokine IL-1bwas found to disrupt microglial clearance functions and to impair the formation of dendritic spines, thereby interfering with memory consolidation (Hickman et al., 2008; Tong et al., 2012).”
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Inflammasome-mediated innate immunity in Alzheimer’s disease
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Neuroprotective Effect of Sulforaphane against Methylglyoxal Cytotoxicity
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The Alzheimer's Amyloid-Degrading Peptidase, Neprilysin: Can We Control It?
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“In the brain, NEP levels are much lower than in the kidney, and it appears to have mostly neuronal localisation [32] although it was recently reported to be expressed by activated astrocytes [33] and microglia [34].”
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Microglia display modest phagocytic capacity for extracellular tau oligomers
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“In early stages of AD, microglia activation becomes protective and delays the disease progression by effective clearance of pathological lesions [55-57], while in the later stages, microglia lose their protective function and release pro-inflammatory cytokines such as tumor necrosis factoralpha (TNF-α) and interleukin…”
BackgroundAction Mechanisms of Curcumin in Alzheimer’s Disease and Its Brain Targeted Delivery
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“Initially, microglia cells remove Aβ aggregates; however, the clearance eventually fails due to chronic inflammation [18,19].”
BackgroundThe Dynamic Role of Microglia and the Endocannabinoid System in Neuroinflammation
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“The increased concentration of these cytokines could exacerbate the accumulation of Aβ and produce further damage to the brain (Hickman et al., 2008).”
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“However, neuronal loss also results from increased proinflammatory cytokine production by microglia.(7) In addition to the influence of microglia, astrocytes could potentially affect Aβ-induced neurotoxicity.”
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Clearance of two organic nanoparticles from the brain via the paravascular pathway
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Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease
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“Amyloid β (Aβ) plaques and hyperphosphorylated tau, which are both pathologic features of AD, are capable of inducing neuroinflammation by activating microglial cells to produce inflamma- tory mediators (Hickman et al., 2008; Kahn et al., 2012; Meda et al., 1995).”
BackgroundAbnormal Changes in NKT Cells, the IGF-1 Axis, and Liver Pathology in an Animal Model of ALS
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Interventions for age-related diseases: Shifting the paradigm
Figueira, I., Fernandes, A. M. A., Mladenović, A., Lopez-Contreras, A. J., Henriques, C. M., Selman, C., Ferreiro, E. B., Gonos, E. S., Trejo, J. L., Misra, J., et al. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.09.009 · Cited by 92
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Human CNS immune senescence and neurodegeneration
Streit, W. J., & Xue, Q.-S. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.05.005 · Cited by 86
Moya, G. E., Rivera, P. D., & Dittenhafer‐Reed, K. E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22137030 · Cited by 90
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“Although maintaining their ability to produce pro-inflammatory cytokines, microglia of aging APP/PS1-transgenic mice, a mouse model of Aβ plaque formation associated with AD, become dysfunctional and display a reduced Aβ clearance capability [12], suggesting that Aβ plaques might partially result from impaired microgl…”
Recent Advances in the Study of Bipolar/Rod-Shaped Microglia and their Roles in Neurodegeneration
Au, N. P. B., & Ma, C. H. E. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00128 · Cited by 87
“…of β-amyloid-binding receptors and β-amyloiddegrading enzymes in the microglia of 14-month-old AD mice were markedly reduced as compared to age-matched wild type littermates; meanwhile, expression of the pro-inflammatory cytokines, IL-1β and TNFα, were elevated inmicroglia (Hickman et al., 2008).”
BackgroundSayed, A., Bahbah, E. I., Kamel, S., Barreto, G. E., Ashraf, G. M., & Elfil, M. (2020) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2020.577398 · Cited by 88
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“However, aging is known to have an effect on inflammation, either due to an increase in the genes associated with aging resulting in a chronic proinflammatory status [41] or due to microglial dysfunction [36, 42].”
Hoeijmakers, L., Heinen, Y., van Dam, A.-M., Lucassen, P. J., & Korosi, A. (2016) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2016.00398 · Cited by 85
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“Contemporary research suggests that elevated cytokine levels in cerebrospinal fluid (CSF) may impair microglial clearance of A β oligomers (Hickman et al., 2008; Guerreiro et al., 2013).”
Cognitive and Behavioral Consequences of Impaired Immunoregulation in Aging
Corona, A. W., Fenn, A. M., & Godbout, J. P. (2011) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-011-9313-4 · Cited by 87
“For example, there was reduced phagocytosis of beta-amyloid by microglia from older AD transgenic mice (Hickman et al. 2008; Lee et al. 2010).”
BackgroundHa, T.-Y., Chang, K.-A., Kim, J. A., Kim, H.-S., Kim, S., Chong, Y. H., & Suh, Y.-H. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008840 · Cited by 73
“A recent report showed that microglia in the brains of aged AD mice became dysfunctional in terms of Ab clearance, and expressions of their Ab-binding receptors and Ab-degrading enzymes were significantly reduced; however, their ability to produce proinflammatory cytokines was maintained [34].”
Senescent Microglia: The Key to the Ageing Brain?
Greenwood, E. K., & Brown, D. R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094402 · Cited by 84
“In addition, a loss of phagocytic ability, which is known to be a feature of senescent or aged cells, has been implicated in the diminished capacity of the brain for clearance of Amyloid β (Aβ) [75,95,115,155], paving the way for formation of amyloid plaques and their spread throughout the brain.”
BackgroundPirzada, R. H., Javaid, N., & Choi, S. (2020) · Genes · doi:10.3390/genes11020131 · Cited by 84
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“Indeed, activated microglia are reported to be associated with the pathogenesis of Parkinson’s disease [1] and Alzheimer’s disease [2].”
BackgroundSimon, E., Obst, J., & Gomez-Nicola, D. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2018.01.059 · Cited by 83
“The expression of IDE, NEP, and MMP-9 has been shown to decline in microglia of aged APP/PS1 mice, which may contribute to their functional impairment in later stages of AD (Hickman et al., 2008).”
BackgroundProteostasis Disturbances and Inflammation in Neurodegenerative Diseases
Sonninen, T.-M., Goldsteins, G., Laham-Karam, N., Koıstınaho, J., & Lehtonen, Š. (2020) · Cells · doi:10.3390/cells9102183 · Cited by 89
“This is associated with the decreased microglial capability to phagocytose Aβ and pro-inflammatory cytokine release [86].”
BackgroundReal-Time Imaging and Quantification of Amyloid-β Peptide Aggregates by Novel Quantum-Dot Nanoprobes
Tokuraku, K., Marquardt, M. M., & Ikezu, T. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008492 · Cited by 87
“[8,9,32].”
Gu, X., Zhou, J., Zhou, Y., Wang, H., Si, N., Ren, W., Zhao, W., Fan, X., Gao, W., Wei, X., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00779-7 · Cited by 81
“So the accumulation of Aβ throughout the brain is the failure of microglia and peripherical monocytes to remove extracellular amyloid [18, 19], which reversely activates microglia and releases inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6 and tumour necrosis factor (TNF-α) [20].”
BackgroundCD36 in Alzheimer’s Disease: An Overview of Molecular Mechanisms and Therapeutic Targeting
Dobri, A.-M., Dudău, M., Enciu, A., & Hinescu, M. E. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.11.003 · Cited by 83
“…reported in vitro, in microglia (Bamberger et al., 2003; Luster et al., 2003; Tsukahara, 2020) and at amyloid sites in mouse and human brains (Moore et al., 2002; El Khoury et al., 2003; Hickman et al., 2008; Park et al., 2017) (for reviews see (Doens and Fernández, 2014; Nichols et al., 2019)).”
Tesco, G., & Lomoio, S. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101628 · Cited by 102
Zheng, T., Pu, J., Chen, Y., Mao, Y., Guo, Z., Pan, H., Zhang, L., Zhang, H., Sun, B., & Zhang, B. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00012 · Cited by 82
“An autopsy study also found marked deposition of gray matter and vascular Aβ in relatively young patients with iatrogenic Creutzfeldt–Jakob disease (Jaunmuktane et al., 2015).”
BackgroundGoncalves, M. B. C. V., Clarke, E. E., Hobbs, C., Malmqvist, T., Deacon, R. M. J., Jack, J., & Corcoran, J. P. T. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12142 · Cited by 81
“It is well known that early microglial recruitment to the amyloid plaques promotes their clearance (Hickman et al., 2008), but the subsequent release of inflammatory cytokines, including TNFa, leads to the downregulation of genes which are involved in the clearance of Ab, such as IDE and NEP…”
InfluentialWan, W., Chen, H., & Li, Y. (2013) · International Journal of Neuroscience · doi:10.3109/00207454.2013.825258 · Cited by 83
“Subsequently in AD, the amount of Aβ exceeds the clearance ability of microglia; the fatal impact is that Aβ-RAGE engagement activates intracellular signaling transduction pathway, which activates microglia and releases inflammatory factors [38, 39].”
BackgroundHickman, S. E., Allison, E. K., Coleman, U., Kingery-Gallagher, N. D., & El Khoury, J. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02780 · Cited by 80
“Amount of Aβ (1-42) and Aβ (1-40) in brain samples was determine using a standard curve of known amounts of human Aβ (1-42) or Aβ (1-40) supplied with the kits.”
BackgroundMethodInfluentialSelf-citationLeko, M. B., Perković, M. N., Klepac, N., Štrac, D. Š., Borovečki, F., Pivac, N., Hof, P. R., & Šimić, G. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200056 · Cited by 80
Loeffler, D. A. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-230025 · Cited by 90
Studying neurodegenerative diseases in culture models
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Dual role of nitric oxide in Alzheimer's disease
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Microglia as a critical player in both developmental and late-life CNS pathologies
Derecki, N. C., Katzmarski, N., Kipnis, J., & Meyer-Luehmann, M. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1321-z · Cited by 78
“For instance, during the progression of AD, the expression of several Aβ binding receptors such as the Scara-1, CD36 and RAGe decreased by two- to fivefold in microglia, and thereby lost their ability to clear Aβ [49].”
BackgroundSárvári, M., Hrabovszky, E., Kalló, I., Solymosi, N., Likó, I., Berchtold, N. C., Cotman, C. W., & Liposits, Z. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-264 · Cited by 81
“Although the microglial response is signal-specific, activated microglia unfold strong macrophage characteristics and express elevated levels of phagocytic [29], scavenger [30] and toll-like [31] receptors (Tlrs), MHC antigens [32].”
BackgroundCroze, M. L., & Zimmer, L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170857 · Cited by 78
“As dysregulated microglia is less efficient to clear the brain from abnormal substances such as A (cid:2) peptide aggregates [103, 104], ozone pollution exposure could also contribute to A (cid:2) peptide accumulation through microglia dysfunction.”
Chen, S., Liu, H., Wang, S., Jiang, H., Gao, L., Wang, L., Teng, L., Wang, C., & Wang, D. (2022) · Nutrients · doi:10.3390/nu14071417 · Cited by 82
“This promotes the aggregation of Aβ plaques that is followed by exacerbation of neuroinflammation and AD pathology [43,48,49].”
BackgroundZhao, Y., Chen, X., Wu, Y., Wang, Y., Li, Y., & Xiang, C. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00140 · Cited by 79
“However, impaired and dysfunctional microglia decrease the capacity of Aβ clearance in AD model mice due to reduced IDE and NEP secretion (Hickman et al., 2008).”
BackgroundShapira, R., Solomon, B., Efrati, S., Frenkel, D., & Ashery, U. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.10.007 · Cited by 80
“Excessive activation of glia due to persistent exposure to proinflammatory cytokines induces synapse loss and neuronal degeneration (Hickman et al., 2008; Iram et al., 2016; Kitazawa et al., 2011; Shi et al., 2011).”
BackgroundWelcome, M. O. (2019) · NeuroMolecular Medicine · doi:10.1007/s12017-019-08547-5 · Cited by 77
Ding, Y., Qiao, A., & Fan, G.-H. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.03.022 · Cited by 75
“, 2003), are down-regulated in APP/PS1 mice (Hickman et al., 2008), our next question was whether IMX reduces Aβ by increasing Aβ degradation enzymes.”
Role of HIV in Amyloid Metabolism
Ortega, M., & Ances, B. M. (2014) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-014-9546-0 · Cited by 78
Induction of Neuronal Death by Microglial AGE-Albumin: Implications for Alzheimer’s Disease
Byun, K., Bayarsaikhan, E., Kim, D., Kim, C. Y., Mook-Jung, I., Paek, S. H., Kim, S. U., Yamamoto, T., Won, M.-H., Song, B.-J., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037917 · Cited by 75
“Several studies reported that AGEs are localized in the senile plaques and extra-cellular spaces [8,9,11,13,16,25].”
BackgroundRivera-Escalera, F., Pinney, J. J., Owlett, L., Ahmed, H., Thakar, J., Olschowka, J. A., Elliott, M. R., & O’Banion, M. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1645-7 · Cited by 75
Cameron, B., Tse, W., Lamb, R., Li, X., Lamb, B. T., & Landreth, G. E. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1729-12.2012 · Cited by 76
“Isolation of adult microglia was performed as previously described (Hickman et al., 2008).”
BackgroundMethodResultInfluentialCastranio, E. L., Hasel, P., Haure‐Mirande, J., Ramirez Jimenez, A. V., Hamilton, B. W., Kim, R. D., Glabe, C. G., Wang, M., Zhang, B., Gandy, S., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12821 · Cited by 74
Fatty acid transporting proteins: Roles in brain development, aging, and stroke
Zhang, W., Chen, R., Yang, T., Xu, N., Chen, J., Gao, Y., & Stetler, R. A. (2017) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2017.04.004 · Cited by 79
Danger-Sensing/Patten Recognition Receptors and Neuroinflammation in Alzheimer’s Disease
Chiarini, A., Armato, U., Hu, P., & Prà, I. D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239036 · Cited by 77
“Moreover, SR-B2/CD36 binds soluble Aβs in vitro [160] and mediates microglial and macrophage responses to Aβs in mice [158].”
BackgroundGray, S. C., Kinghorn, K. J., & Woodling, N. S. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.272571 · Cited by 76
“However, these microglial activities are subject to an age-related, Aβ-contingent decline, coincident with a two- to five-fold downregulation in Aβ-degrading enzymes, namely neprilysin, insulin-degrading enzyme and matrix metalloprotease-9, as well as in scavenger receptors known to recognize Aβ, including receptors f…”
Background
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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