Microglia in Alzheimer's disease
Open accessAbstract
Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an "activated state"). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer's disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed.
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- Premisecitation
PRRs bind different species of amyloid-beta with varying affinities.
“PRRs bind to different species of Aβ with various affinities (71).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [71] source
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- Premisecitation
Microglial-derived immune factors can induce an A1 astrocyte phenotype that contributes to neuronal death through reduced trophic support, impaired clearance, and release of toxins.
“Microglial-derived immune factors can induce a so-called A1 astrocyte phenotype that contributes to neuronal death through reduced trophic support, impaired clearance capacity, and release of toxins (69).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] source
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- Premisecitation
Activated microglia, immunoglobulins, and complement components are closely associated with amyloid-beta deposits in Alzheimer's disease patients and mouse models.
“Activated microglia along with immunoglobulins and complement components are closely associated with Aβ deposits in brains from AD patients and AD mouse models (58)(59)(60)(61)(62).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Microglia are implicated in spreading tau aggregates through endocytosis and exocytosis in a nonsynaptic transmission pathway.
“microglia also were implicated in spreading tau aggregates through endocytosis (via phagocytosis) and exocytosis (via exosomes) in a nonsynaptic transmission pathway (68).”
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- Premisecitation
Amyloid-beta-mediated release of proinflammatory factors and neurotoxicity partially involves signaling through the CD36/TLR4/TLR6 complex.
“Stewart and colleagues demonstrated that Aβ-mediated release of proinflammatory factors and neurotoxicity partially involved signaling through the CD36/ TLR4/TRL6 complex (108).”
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- Premisecitation
TLRs bind both fibrillar and oligomeric forms of amyloid-beta.
“TLRs bind both fibrillar and oligomeric forms of Aβ (74).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [74] Landreth, 2009, Toll-like receptors in Alzheimer’s disease, Curr Top Microbiol Immunol
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- Premisecitation
GWAS link immune genes CR1, CD33, and TREM2 to increased Alzheimer's disease risk.
“recent GWAS link several immune genes, particularly complement receptor-1 (CR1), CD33, and triggering receptor expressed on myeloid cells-2 (TREM2), with increased AD risk (55).”
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- Interpretationcitation
Innate immune activation may actively contribute to Alzheimer's disease pathogenesis rather than being only a bystander reaction to amyloid deposition.
“These findings raise the possibility that innate immune activation may actively contribute to AD pathogenesis, rather than arising as a pure bystander reaction to amyloid deposition, as previously assumed (57).”
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- Premisecitation
A network-based integrative analysis found that an immune/microglial gene network had the strongest association with Alzheimer's disease neuropathology.
“a network-based integrative analysis of AD-related genes revealed that an immune/microglial gene network had the strongest association with AD neuropathology (56).”
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- Premisecitation
APOE4 expression is associated with enhanced amyloid-beta production through increased APP expression in neurons.
“APOE4 expression was associated with enhanced Aβ production, driven by increasing APP expression in neurons (54).”
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- Premisecitation
Studies on the role of TLRs in microglial activation have produced conflicting results.
“studies elucidating the role of TLRs in microglial activation have yielded conflicting results (109).”
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- Premisecitation
Epidemiological studies support that NSAIDs decrease the development of Alzheimer's disease.
“epidemiological studies supported that NSAIDs decrease the development of AD (105).”
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- Interpretationcitation
Microglial activation in the Alzheimer's disease trajectory may follow a bimodal distribution, with an early protective peak at the preclinical/prodromal stage and a later proinflammatory phenotype peaking at the clinical stage.
“Taken together, the authors suggested a bimodal distribution of microglial activation in the trajectory of AD, with an early protective peak at the preclinical/prodromal stage and a later cidal proinflammatory phenotype peaking at the clinical stage (102).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [102] Fan, 2017, An early and late peak in microglial activation in Alzheimer’s disease trajectory, Brain
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- Premisecitation
TLR4 stimulation increases tau-related pathology in 3xTgAD and rTg4510 mice.
“A drawback of TLR4 stimulation was the observed increase in taurelated pathology in 3xTgAD and rTg4510 mice (109).”
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- Premisecitation
In mild cognitive impairment, microglial activation is positively correlated with cognition and gray matter volume, suggesting a protective role in the early phase of clinically apparent disease.
“in MCI, microglial activation was positively correlated with cognition and gray matter volume, suggesting that microglial activation plays a protective role in the early phase of clinically apparent disease (100).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [100] Hamelin, 2016, Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging, Brain source
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- Premisecitation
In a mouse model of Alzheimer's disease, overexpression of CRRY, C3 deficiency, or blocking C5a increases amyloid-beta levels without increased production, reflecting the role of complement in microglial phagocytosis.
“In a mouse model of AD, overexpression of soluble complement component 3b/4b receptor 1-like (CRRY; a complement inhibitor in rodents) (122), C3 deficiency (123), or blocking of C5a (124), a downstream component of the complement cascade, increased Aβ levels in the absence of increased Aβ production, reflecting the role of complement in microglial phagocytosis.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Microglia in concert with complement cause early synapse loss when challenged with oligomeric amyloid-beta.
“Hong and colleagues demonstrated that microglia in concert with complement caused early synapse loss when challenged with oligomeric Aβ (121).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [121] source
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- Interpretationreasoning
Discrepancies among complement studies underscore the impact of the precise disease time period on complement-mediated regulation of microglia.
“The discrepancies among these studies underscore the impact of the precise disease time period on complement-mediated regulation of microglial”
Quote in the paperSubstantial claim - Premisecitation
Blocking C3, C1q, or CR3 rescues early synapse loss in APP/PS1 mice.
“Blocking of C3, C1q, or CR3 rescued this early synapse loss in APP/PS1 mice (121).”
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- Premisecitation
Before amyloid-beta deposition, microglia engulf synapses opsonized with C1q and C3 upon CR3-mediated recognition of C3.
“Before the onset of Aβ deposition, microglia engulf synapses opsonized with the complement factors C1q and C3 upon CR3-mediated recognition of C3 (121).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [121] source
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Complement blockade is associated with increased neurodegeneration.
“In the same studies, complement blockade was associated with increased neurodegeneration.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Complement-mediated microglial phagocytosis of synapses may contribute to Alzheimer's disease pathogenesis.
“Given the role of microglia and complement in synaptic pruning and the identification of a CR1 gene variant that is linked to an increased risk for AD (17, 120), complement-mediated microglial phagocytosis of synapses may contribute to AD pathogenesis.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Cytokines could serve as potential therapeutic targets to modulate microglial responses.
“Thus, cytokines could serve as potential therapeutic targets to modulate microglial responses.”
Quote in the paperSubstantial claim - Premisecitation
Inhibition of the proinflammatory response, including loss of NLRP3 inflammasome, MRP14, and IL-12/IL-23 signaling, is beneficial in reducing amyloid pathology.
“the inhibition of proinflammatory response, including loss of NLRP3 inflammasome, myeloid-related protein-14 (MRP14), and IL-12 and IL-23 signaling, has also been beneficial in reducing amyloid pathology (130).”
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- Interpretationcitation
The striking difference between human and mouse microglial renewal supports the idea that rodent microglia may not experience aging-associated pathological factors such as senescence or dystrophy.
“This striking difference between human and mouse supports the idea that rodent microglia may not experience pathological factors associated with aging such as senescence or dystrophy (70).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [70] Streit, 2014, Microglial pathology, Acta Neuropathol Commun source
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- Premisecitation
Mice overexpressing IL-6 or IFN-γ show enhanced microglial phagocytosis of amyloid-beta accompanied by increased complement component mRNA, TNF-α, and other inflammatory mediators.
“mice overexpressing IL-6 (127) or IFN-γ (128) had enhanced microglial phagocytosis of Aβ accompanied by an increase in complement component mRNA levels, TNF-α, and other inflammatory mediators.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
CSF1R signaling in a selected neuron population, rather than in microglia, provides neuroprotective and survival signals in the neurodegeneration setting.
“CSF1R signaling in a selected neuron population, rather than in microglia, provides neuroprotective and survival signals in the neurodegeneration setting (146).”
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- Premisecitation
Stimulation of nuclear receptor signaling with the retinoid X receptor agonist bexarotene induces TREM2 expression in microglia.
“Stimulation of nuclear receptor signaling with the retinoid X receptor agonist bexarotene induces the TREM2 expression in microglia (153).”
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- Premisecitation
Allelic variants of TREM2 confer high risk for developing sporadic Alzheimer's disease.
“Allelic variants of TREM2 confer high risk for developing sporadic AD; therefore, research into TREM2's function has gained momentum.”
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Microglia receive survival and proliferation signals following stimulation of CSF1R with CSF1 or IL-34.
“Microglia receive signals for survival and proliferation following stimulation of the CSF1 receptor (CSF1R) with CSF1 or IL-34 (142).”
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- Premisecitation
TREM2 has many ligands, including phospholipids, sulfatides, lipoprotein particles such as HDL and LDL, and APOE.
“TREM2 has many ligands, including phospholipids and sulfatides, which are exposed on apoptotic or damaged cells, lipoprotein particles such as HDL and LDL, and APOE.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
In Alzheimer's disease patients, TREM2 amounts are higher in microglia, especially those linked to plaques and neurofibrillary changes.
“TREM2 levels were elevated in the microglia of AD patients, particularly in microglia associated with plaques and neurofibrillary changes, and TREM2 levels correlated with markers of neurodegeneration (154), suggesting a pathogenic role for TREM2.”
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- Interpretationcitation
TREM2 has a pathogenic role.
“TREM2 levels were elevated in the microglia of AD patients, particularly in microglia associated with plaques and neurofibrillary changes, and TREM2 levels correlated with markers of neurodegeneration (154), suggesting a pathogenic role for TREM2.”
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- Premisecitation
TREM2 amounts show a correlation with neurodegeneration markers.
“TREM2 levels were elevated in the microglia of AD patients, particularly in microglia associated with plaques and neurofibrillary changes, and TREM2 levels correlated with markers of neurodegeneration (154), suggesting a pathogenic role for TREM2.”
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- Premisecitation
In Alzheimer's disease mice, myeloid cells that express TREM2 are concentrated in microglial processes that touch amyloid deposits.
“TREM2 deficiency eliminated plaque-associated CD45 hi LyC + myeloid cells, leading to reduced inflammation and AD-like pathology in these mice (155); however, TREM2-expressing myeloid cells were enriched in microglia processes contacting amyloid deposits in AD mice, and TREM2 deletion resulted in less compact plaques and increased dystrophic neurites.”
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- Premisecitation
Deleting TREM2 leads to plaques that are less compact.
“TREM2 deficiency eliminated plaque-associated CD45 hi LyC + myeloid cells, leading to reduced inflammation and AD-like pathology in these mice (155); however, TREM2-expressing myeloid cells were enriched in microglia processes contacting amyloid deposits in AD mice, and TREM2 deletion resulted in less compact plaques and increased dystrophic neurites.”
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- Premisecitation
Loss of TREM2 removes CD45hi LyC+ myeloid cells that are associated with plaques in Alzheimer's disease mice.
“TREM2 deficiency eliminated plaque-associated CD45 hi LyC + myeloid cells, leading to reduced inflammation and AD-like pathology in these mice (155); however, TREM2-expressing myeloid cells were enriched in microglia processes contacting amyloid deposits in AD mice, and TREM2 deletion resulted in less compact plaques and increased dystrophic neurites.”
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- Premisecitation
Certain TREM2 variants can either weaken or strongly strengthen TREM2's interaction with phospholipids.
“AD risk variants in TREM2 impair the cell surface transport and expression of TREM2; some variants either impair or markedly enhance the binding of TREM2 to phospholipids, suggesting that balanced TREM2 function in AD is important to counteract disease progression (147).”
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- Premisecitation
Research on TREM2 deficiency in Alzheimer's disease mouse models has yielded inconsistent findings, with some reports showing increased and others decreased Aβ pathology.
“Studies on TREM2 deficiency in AD mice have produced conflicting results, with reports that Aβ pathology could be either increased or decreased.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
Maintaining a balanced level of TREM2 activity in Alzheimer's disease is important for opposing disease progression.
“AD risk variants in TREM2 impair the cell surface transport and expression of TREM2; some variants either impair or markedly enhance the binding of TREM2 to phospholipids, suggesting that balanced TREM2 function in AD is important to counteract disease progression (147).”
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- Premisecitation
Deleting TREM2 leads to more dystrophic neurites.
“TREM2 deficiency eliminated plaque-associated CD45 hi LyC + myeloid cells, leading to reduced inflammation and AD-like pathology in these mice (155); however, TREM2-expressing myeloid cells were enriched in microglia processes contacting amyloid deposits in AD mice, and TREM2 deletion resulted in less compact plaques and increased dystrophic neurites.”
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- Premisecitation
Silencing TREM2 in P301S mice leads to greater synapse loss.
“Similarly, TREM2 silencing in P301S mice increased tau pathology and synapse loss and enhanced the proinflammatory cytokine levels in the brain (156).”
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- Premisecitation
These amyloid reductions accompany an increase in the number of microglia.
“Interestingly, entraining gamma oscillation at 40 Hz in 5xFAD mice induced amyloid reductions that were associated with an increase in microglial numbers and morphological changes such as soma enlargement and shortening of processes loaded with Aβ.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [158] source
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- Premisecitation
In aged APP/PS1-21 mice, TREM2 deficiency increases amyloid deposition.
“While TREM2 deficiency in young APP/PS1-21 mice ameliorated amyloid pathology, it enhanced amyloid deposition at later disease stages (157).”
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- Premisecitation
In aged mice, TREM2 deficiency reduces the buildup of plaque-associated myeloid cells.
“Additionally, TREM2 deficiency in aged mice decreased plaque-associated myeloid cell accumulation by reducing proliferation (157).”
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- Premisecitation
Driving gamma oscillations at 40 Hz in 5xFAD mice leads to reductions in amyloid.
“Interestingly, entraining gamma oscillation at 40 Hz in 5xFAD mice induced amyloid reductions that were associated with an increase in microglial numbers and morphological changes such as soma enlargement and shortening of processes loaded with Aβ.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [158] source
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- Premisecitation
In young APP/PS1-21 mice, TREM2 deficiency reduces amyloid pathology.
“While TREM2 deficiency in young APP/PS1-21 mice ameliorated amyloid pathology, it enhanced amyloid deposition at later disease stages (157).”
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- Interpretationcitation
The conflicting findings from earlier studies may be explained by TREM2 deficiency affecting Alzheimer's pathology differently depending on disease stage.
“A recent report indicated that the opposing results from previous work might reflect a disease progression-dependent influence of TREM2 deficiency on AD pathology.”
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- Premisecitation
Silencing TREM2 in P301S mice worsens tau pathology.
“Similarly, TREM2 silencing in P301S mice increased tau pathology and synapse loss and enhanced the proinflammatory cytokine levels in the brain (156).”
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- Premisecitation
Silencing TREM2 in P301S mice raises the levels of proinflammatory cytokines in the brain.
“Similarly, TREM2 silencing in P301S mice increased tau pathology and synapse loss and enhanced the proinflammatory cytokine levels in the brain (156).”
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- Premisecitation
RNA sequencing revealed higher expression of phagocytic genes, including Cd68, B2m, Icam, and Lyz2.
“RNA sequencing analysis showed an increase in phagocytic genes, such as Cd68, β 2 -microglobulin (B2m), Icam, and lysozyme 2 (Lyz2), and in the proliferation markers Csf1, Csf1r, and Csf2ra.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [158] source
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- Premisecitation
This reduction in plaque-associated myeloid cell accumulation results from less proliferation.
“Additionally, TREM2 deficiency in aged mice decreased plaque-associated myeloid cell accumulation by reducing proliferation (157).”
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- Premisecitation
The expression of proinflammatory genes Il1b, Il6, and Cd11b and the antiinflammatory gene Igf1 remained unchanged.
“Notably, levels of proinflammatory genes (Il1b, Il6, Cd11b) and antiinflammatory genes (Igf1) were not changed (158), suggesting that it is possible to use immunomodulation to polarize microglia toward a beneficial activation state that is characterized by increased phagocytic activity without the induction of sustained inflammatory responses.”
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- Interpretationreasoning
Microglia may be activated to enhance Aβ clearance and lessen amyloid deposition via several mechanisms.
“Although the data are not fully consistent, they strongly suggest that microglia could be mobilized to promote Aβ clearance and reduce amyloid deposition through multiple mechanisms.”
Quote in the paperSubstantial claim - Premisecitation
RNA sequencing also showed higher expression of proliferation markers Csf1, Csf1r, and Csf2ra.
“RNA sequencing analysis showed an increase in phagocytic genes, such as Cd68, β 2 -microglobulin (B2m), Icam, and lysozyme 2 (Lyz2), and in the proliferation markers Csf1, Csf1r, and Csf2ra.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [158] source
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- Interpretationnone given
Microglia appear to play a close role in spreading tau pathology.
“Interestingly, microglia seem to be intimately involved in the propagation of tau pathology; however, it remains unclear whether microglia contribute to tau pathology by failing to phagocytize pathological tau or by releasing factors that exacerbate tau pathology.”
Quote in the paperSubstantial claim - Premisenone given
Neuroinflammation plays opposing roles in the early and late stages of Alzheimer's disease.
“A plethora of evidence supports the dual nature of neuroinflammation in the early versus the late phases of AD.”
Quote in the paperSubstantial claim - Interpretationreasoning
Depending on the disease context, M1 or M2 microglial phenotypes may be harmful or helpful.
“Additionally, the M1 or M2 microglia phenotypes could have a detrimental or beneficial outcome depending on the disease context, and more detailed analysis is required.”
Quote in the paperSubstantial claim - Interpretationcitation
Immunomodulation can shift microglia toward a beneficial activation state with increased phagocytic activity and without prolonged inflammatory responses.
“Notably, levels of proinflammatory genes (Il1b, Il6, Cd11b) and antiinflammatory genes (Igf1) were not changed (158), suggesting that it is possible to use immunomodulation to polarize microglia toward a beneficial activation state that is characterized by increased phagocytic activity without the induction of sustained inflammatory responses.”
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- May combine two claims. 35
- Classified as probably not a substantial claim. 4
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PremisecitationIncreased expression of Tlr2, Tlr4, Tlr5, Tlr7, and Tlr9 mRNAs is found in amyloid-beta plaques, and Tlr2/5 expression is elevated in plaque-associated tissue compared with plaque-free tissue.
“Increased expression of Tlr2, Tlr4, Tlr5, Tlr7, and Tlr9 mRNAs was found in Aβ plaques, and expression of Tlr2/5 was elevated in plaque-associated tissue in comparison with plaquefree tissue (107)”
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InterpretationcitationDepletion of microglia suppresses tau propagation, suggesting that microglia actively contribute to tau pathology during Alzheimer's disease pathogenesis.
“Depletion of microglia suppressed tau propagation (68), suggesting that microglia actively contribute to tau pathology during AD pathogenesis.”
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InterpretationreasoningMicroglial activation in Alzheimer's disease pathogenesis may have a dual role: acute activation decreases amyloid-beta accumulation, while chronic activation contributes to neurotoxicity and synapse loss.
“In AD pathogenesis, microglia activation may play a dual role: on one side, acute microglial activation in some experimental paradigms leads to decreased Aβ accumulation by increasing phagocytosis or clearance.”
- Also stated in: § Alzheimer's disease · plain
“chronic activation of microglia contributes to neurotoxicity and synapse loss by triggering several proinflammatory cascades.”
Quote in the paperSubstantial claim- Also stated in: § Alzheimer's disease · plain
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PremisecitationActivated microglia in Alzheimer's disease show increased proliferation and increased expression of inflammatory markers such as CD36, CD14, CD11c, MHC-II, and iNOS.
“activated microglia in AD show increased proliferation (63,64) and increased expression of inflammatory markers such as CD36, CD14, CD11c, MHC-II, and iNOS (65,66)”
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- cites [64] Olmos-Alonso, 2016, Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology, Brain source
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- cites [65] Kamphuis, 2016, Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer’s disease, Biochim Biophys Acta source
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PremisecitationIn vivo imaging shows that microglial activation precedes the onset of Alzheimer's disease and is paralleled by increased levels of inflammatory markers in cerebrospinal fluid.
“In vivo imaging shows that microglia activation precedes the onset of AD (100) and is paralleled by increased levels of inflammatory markers in the cerebrospinal fluid (101)”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThe COX-1 inhibitor naproxen is beneficial only in fast decliners, whereas the selective COX-2 inhibitor celecoxib is beneficial in slow decliners but harmful in the fast-progressing group.
“the COX-1 inhibitor naproxen was beneficial in fast decliners only; in contrast, the selective COX-2 inhibitor celecoxib was beneficial in slow decliners but harmful in the fast-progressing group.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [105] source
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PremisecitationRepeated monthly injections of CpG-ODNs for TLR9 stimulation reduce amyloid deposition and cerebral amyloid angiopathy and prevent cognitive deficits in mice.
“repeated monthly injections of CpG-ODNs reduced amyloid deposition and cerebral amyloid angiopathy, and prevented cognitive deficits.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [116] source
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InterpretationcitationCD14 deletion shifts microglial activation toward an immunomodulatory state, possibly by blocking TLR2 signaling that contributes to inflammation and Alzheimer's disease pathology.
“These findings suggested that CD14 deletion shifts microglia activation to an immunomodulatory state, possibly by blocking TLR2 signaling, which contributes to inflammation and AD pathology (115).”
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PremisecitationTLR9 stimulation decreases tau-related pathology, in contrast to TLR4 stimulation.
“In contrast to TLR4 stimulation, TLR9 stimulation decreased tau-related pathology (116).”
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PremisecitationCOX-2 expression peaks in neurons during Braak phases 0-II, probably representing an adaptive response that subsequently declines.
“COX-2 expression peaks in neurons in Braak phases 0-II (an early stage characterized by neurofibrillary changes beginning at transentorhinal regions), probably representing an adaptive response that subsequently declines (105).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [105] source
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PremisecitationIn Alzheimer's disease patients, microglial activation correlates with glucose hypometabolism, suggesting a link between microglial activation and synaptic dysfunction.
“microglial activation correlated with glucose hypometabolism in AD patients (103), suggesting a link between microglial activation and synaptic dysfunction.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Fan, 2015, Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease, Brain source
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InterpretationreasoningTLR9 stimulation activates an innate immune response that benefits Alzheimer's disease pathology without provoking inflammation.
“Hence, it seems that TLR9 stimulation activates an innate immune response that benefits AD pathology without provoking inflammation.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAPP/PS1dE9 mice lacking functional TLR4 show increased amyloid-beta load, decreased IL-1β, CCL3, and CCL4 expression, and decreased cognitive function, suggesting a protective role for TLR4 in amyloid clearance.
“APP/PS1dE9 mice lacking functional TRL4 showed an increase in Aβ load associated with decreased expression of IL-1β, CCL3, and CCL4 and decreased cognitive function (110), suggesting a protective role of TRL4 in amyloid clearance.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [110] Song, 2011, TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease, J Neuroinflammation source
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PremisecitationInhibition of different complement components impairs amyloid-beta phagocytosis and results in elevated synapse loss.
“other studies have reported that inhibition of different components of complement impaired Aβ phagocytosis, resulting in elevated synapse loss.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationInhibition of microglial C3aR reduces microglial activation and augments amyloid-beta clearance, suggesting a detrimental role for complement.
“Inhibition of microglial C3aR reduced microglial activation and augmented Aβ clearance in the brain (125), suggesting a detrimental role for complement.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [125] source
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PremisecitationIn the clinical phase of Alzheimer's disease, a strong association between microglial activation and AD pathology is observed in young patients, but activation wanes in patients older than 80 years.
“in the clinical phase of AD, the strong association between microglial activation and AD pathology was observed in young AD patients, but activation waned in AD patients older than 80 years (106)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [106] Hoozemans, 2011, Neuroinflammation in Alzheimer’s disease wanes with age, J Neuroinflammation source
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PremisecitationAmyloid-beta induces release of C3 from astrocytes and impairs microglial amyloid-beta phagocytosis.
“Lian and colleagues demonstrated that Aβ induced release of C3 from astrocytes and impaired microglial Aβ phagocytosis (125).”
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PremisecitationIL-1β enhances amyloid-beta pathology and increases tau pathology.
“IL-1β, a key cytokine of the innate immune response, was shown to enhance Aβ pathology (126), as well as increase tau pathology (109).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThe NLRP3 inflammasome is critical for maturation of IL-1β, and loss of NLRP3 in APP/PS1 mice decreases amyloid burden.
“The NLRP3 inflammasome is critical for maturation of IL-1β, and loss of NLRP3 in APP/PS1 decreased amyloid burden (131).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [131] Heneka, 2013, NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice, Nature source
Not checked in the free run.
May combine two claims.
PremisecitationIncreased microglial proliferation is observed in several murine Alzheimer's disease models, appearing with plaque onset and persisting for 18 months.
“Increased microglial proliferation was observed in several murine AD models (63), appearing with plaque onset and persisting for 18 months (63).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [63] source
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PremisecitationThe microglial turnover rate in healthy brain was reported as 0.05% at any given time, but recent data from the same group indicate a turnover rate of 0.69%.
“Lawson and colleagues reported a microglial turnover rate of 0.05% at any given time in healthy brain (141), but recent data from the same group indicated a turnover rate of 0.69% (7).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIL-10 levels are elevated in Alzheimer's disease brain, and IL-10 overexpression in mice increases APOE expression and worsens AD-related pathology and cognitive impairment.
“IL-10 levels are elevated in AD brain, and IL-10 overexpression in mice increased APOE expression in addition to worsening AD-related pathology and cognitive impairment (132).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [132] source
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PremisecitationMicroglia from TNFR-deficient 3xTgAD mice show defective phagocytosis, highlighting a protective role for TNF-α in clearance mechanisms.
“microglia from TNFR-deficient 3xTgAD mice showed defective phagocytosis, highlighting the protective role of TNF-α in facilitating clearance mechanisms.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [129] source
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PremisecitationIl10 deletion leads to increased amyloid-beta phagocytosis and increased CD68 reactivity in amyloid-beta deposit-associated microglia.
“Il10 deletion led to increased Aβ phagocytosis and increased CD68 reactivity in Aβ depositassociated microglia (133).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [133] source
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PremisecitationIncreased microglial proliferation is described in the brains of Alzheimer's disease patients and in the prodromal stage of Parkinson disease, suggesting that microglial proliferation is an early event in neurodegenerative diseases.
“Increased microglial proliferation has been described in the brains of AD patients (135), and in the prodromal stage of Parkinson disease (136), suggesting that microglial proliferation is an early event in the course of neurodegenerative diseases.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationTNFR deficiency in 3xTgAD mice is associated with increased amyloid deposition and enhanced tau phosphorylation.
“TNF receptor (TNFR) deficiency in 3xTgAD mice was associated with increased amyloid deposition and enhanced tau phosphorylation (129).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [129] source
Not checked in the free run.
May combine two claims.
PremisecitationTREM2 deficiency impairs microglial phagocytosis of plaques opsonized with anti-amyloid-beta antibodies, suggesting a critical role for TREM2 in the efficacy of antibody-based therapeutics.
“TREM2 deficiency impairs microglial phagocytosis of plaques opsonized with anti-Aβ antibodies, suggesting a critical role for TREM2 in the efficacy of antibody-based therapeutics (152).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [152] source
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PremisecitationTREM2 promotes phagocytosis of apoptotic neurons, proliferation, and survival of microglia, and dampens TLR-induced inflammatory responses.
“TREM2 promotes phagocytosis of apoptotic neurons, proliferation, and survival of microglia, and has been implicated in dampening TLR-induced inflammatory responses (147-151).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe CEBP/α/PU.1 pathway is involved in regulating monopoiesis and granulopoiesis and is a candidate for regulating microglial proliferation.
“the CEBP/α/PU.1 pathway is involved in the regulation of monopoiesis and granulopoiesis (143, 144) and serves as a candidate for regulating proliferation in microglia.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationPharmacological inhibition of CSF1R in mice upregulates antiinflammatory mediators, increases synapse and spine densities, and reduces proinflammatory cytokine levels.
“Pharmacological inhibition of CSF1R in mice upregulated antiinflammatory mediators, including IL-4, IL-5, IL-13, and CCL9, and increased synapse and spine densities while reducing proinflammatory cytokine levels (64).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] Olmos-Alonso, 2016, Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology, Brain source
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InterpretationcitationTargeting CSF1R has therapeutic potential, but caution is warranted because CSF1R haploinsufficiency is linked to adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
“Although targeting CSF1R has therapeutic potential, caution should be taken, as CSF1R haploinsufficiency was linked to adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (145).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [145] source
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May combine two claims.
PremisecitationTREM2 expression is increased in CD45hi LyC+ myeloid cells around amyloid plaques, but not in parenchymal P2Y12+ microglia.
“TREM2 was upregulated in CD45 hi LyC + myeloid cells surrounding the amyloid plaques, but not in parenchymal P2Y12 + microglia (155).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [155] source
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PremisecitationCertain Alzheimer's disease risk variants in TREM2 reduce TREM2's transport to the cell surface and its expression.
“AD risk variants in TREM2 impair the cell surface transport and expression of TREM2; some variants either impair or markedly enhance the binding of TREM2 to phospholipids, suggesting that balanced TREM2 function in AD is important to counteract disease progression (147).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [147] source
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May combine two claims.
PremisecitationIn these mice, the removal of those plaque-associated myeloid cells results in less inflammation and less Alzheimer's-like pathology.
“TREM2 deficiency eliminated plaque-associated CD45 hi LyC + myeloid cells, leading to reduced inflammation and AD-like pathology in these mice (155); however, TREM2-expressing myeloid cells were enriched in microglia processes contacting amyloid deposits in AD mice, and TREM2 deletion resulted in less compact plaques and increased dystrophic neurites.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [155] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAltered gamma oscillations have been found in neurological disorders.
“Gamma oscillations arise from the activation of local circuits of excitatory and fast-spiking inhibitory neurons resonating at 20-50 Hz, and changes in gamma oscillation have been observed in neurological diseases (158).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [158] source
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PremisecitationThese amyloid reductions accompany morphological changes, including enlarged soma and shortened processes filled with Aβ.
“Interestingly, entraining gamma oscillation at 40 Hz in 5xFAD mice induced amyloid reductions that were associated with an increase in microglial numbers and morphological changes such as soma enlargement and shortening of processes loaded with Aβ.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [158] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGamma oscillations are generated by local circuits of excitatory and fast-spiking inhibitory neurons that resonate at 20-50 Hz.
“Gamma oscillations arise from the activation of local circuits of excitatory and fast-spiking inhibitory neurons resonating at 20-50 Hz, and changes in gamma oscillation have been observed in neurological diseases (158).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [158] source
Not checked in the free run.
Classified as probably not a substantial claim.
InterpretationcitationPairing human iPSC technology with recent gene-editing advances will create new ways to model pathology that better mimics human Alzheimer's disease.
“It seems that combining human induced pluripotent stem cell (iPSC) technology (159) with recent advances in gene editing will provide new opportunities to model disease pathology that more closely resembles human AD.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [159] source
Not checked in the free run.
- The authors state this as an assumption: Existing mouse models do not show clear neurodegeneration or human-like tau pathology unless a tau mutation is used to induce the disease.
The authors state this as an assumption.
Aging strongly affects innate immunity and is a major risk factor for Alzheimer's disease.
“Given that age has a dramatic impact on innate immunity and represents a major risk factor for AD, more longitudinal studies need to be performed and the overall outcome of immune modulation needs to be tested in aged animals.”
The authors state this as an assumption.
Existing mouse models do not show clear neurodegeneration or human-like tau pathology unless a tau mutation is used to induce the disease.
“One limitation of current mouse models is the absence of clear neurodegeneration and human-like tau pathology unless the disease is induced by a tau mutation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Neuroinflammation is a key contributor to Alzheimer's disease progression; prolonged activation of microglia and astrocytes leads to chronic inflammation and release of pro-inflammatory cytokines such as IL-1β and TNF-α, promoting neuronal damage in vulnerable brain regions like the neocortex and hippocampus.
“Neuroinflammation is a key contributor to AD progression. While early immune responses may aid in the clearance of Aβ and tau aggregates, prolonged activation of microglia and astrocytes leads to chronic inflammation and the release of pro-inflammatory cytokines such as IL-1β and TNF-α, promoting neuronal damage in vulnerable brain regions like the neocortex and hippocampus [34–36].”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [34]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMicroglia facilitate Aβ clearance through phagocytosis and can also exacerbate neurodegeneration by driving persistent neuroinflammation.
“For example, they facilitate the clearance of Aβ through phagocytosis42, yet they can also exacerbate neurodegeneration by driving persistent neuroinflammation43.”
From Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models (2026) · cites this paper as [43]
Microglia are brain-resident innate immune effector cells and are widely thought to be the key mediators of amyloid beta clearance.
“Microglia are brain-resident innate immune effector cells and are widely thought to be the key mediators of amyloid beta clearance [14–16].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [15]
AD is characterized by the hallmark pathology comprised of widespread amyloid-β (Aβ) deposition, neurofibrillary tangle (NFT) formation, extensive neurodegeneration, and profound activation of microglia in the brain.
“Alzheimer's disease (AD) is characterized by the hallmark pathology comprised of widespread amyloid-β (Aβ) deposition, neurofibrillary tangle (NFT) formation, extensive neurodegeneration, and profound activation of microglia in the brain (6).”
From Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease (2017) · cites this paper as [6]
In the early stages of AD, activated microglia cause phagocytosis and clearance of pathologic Aβ and/or tau, positively affecting AD pathologies in animal models.
“In the early stages of AD, activated microglia cause phagocytosis and clearance of pathologic Aβ and/or tau, positively affecting AD pathologies in animal models [89, 90].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [89]
Microglia exert protective function by phagocytosing and clearing pathological protein aggregates.
“Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [2]
Microglia phagocytose misfolded proteins, cellular debris, and dying cells to maintain homeostasis.
“Microglia phagocytose misfolded proteins, cellular debris, and dying cells to maintain homeostasis.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [2]
Reactive gliosis and neural inflammation are hallmarks of AD, and although microglia are not the primary initiator of AD, they play an important cell-autonomous role in the disease.
“Reactive gliosis and neural inflammation are hallmarks of AD4,122–125.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [4]
Microglia are innate immune cells of the CNS that play important disease-modifying roles in neurodegeneration, including Alzheimer's disease.
“Microglia represent innate immune cells of the CNS that play important disease-modifying roles in neurodegeneration including Alzheimer’s disease (AD) [1–4].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [3]
Mouse model data suggest dual roles for microglia in Alzheimer's disease: pro-inflammatory functions promote neurotoxicity and amyloid β accumulation, opposed by amyloid-clearing and neuroprotective functions.
“Data from mouse models have suggested dual roles for microglia in AD: pro-inflammatory functions that promote neurotoxicity and amyloid β (Aβ) accumulation, opposed by amyloid-clearing and neuroprotective functions [3, 4].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [3]
Aβ accumulation activates microglia and promotes pro-inflammatory mediator production and impairment of their phagocytic function.
“Aβ accumulation activates the microglia and promotes pro-inflammatory mediators’ production and impairment of their phagocytic function (232, 233).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [232]
Colocalization of reactive microglia with Aβ deposits is a hallmark of Alzheimer's disease pathology and has been reported in brains from AD mouse models.
“Colocalization of reactive microglia with Aβ deposits is a hallmark of AD pathology and has been reported also in brains from AD mouse models [102,103].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [102]
Proliferation and activation of microglia in the brain around amyloid plaques is a prominent characteristic of Alzheimer's disease.
“Proliferation and activation of microglia in the brain, around amyloid plaques, is a prominent characteristic of AD [102].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [102]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
COX-2 treatment result conflicts with the proposed disease-stage effect
MinorThe paper places slow decliners earlier in the disease trajectory and says the selective COX-2 inhibitor celecoxib benefited them. It later suggests that blocking COX-2 in early phases may be harmful.
“the selective COX-2 inhibitor celecoxib was beneficial in slow decliners but harmful in the fast-progressing group.”
“Thus, COX-2 blockade in early phases may be harmful, whereas COX-1 inhibition (in addition to COX-2 inhibition) may be beneficial”
C5a blockade effect conflicts with the cited reference title
MinorThe text says blocking C5a increased Aβ levels and associates complement blockade with increased neurodegeneration, citing reference 124. That reference's title instead reports decreased pathology after antagonizing the C5a receptor.
“blocking of C5a (124), a downstream component of the complement cascade, increased Aβ levels in the absence of increased Aβ production, reflecting the role of complement in microglial phagocytosis.In the same studies, complement blockade was associated with increased neurodegeneration.”
“124. Fonseca MI, et al. Treatment with a C5aR antago- nist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease.”
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- Authors
- Sarlus, H., & Heneka, M. T.
- Affiliations
- University of Bonn (DE)
- Corresponding author
- Heneka, Michael T.
- Venue
- Journal of Clinical Investigation
- Published
- 2017-09-01
- Volume
- 127
- Issue
- 9
- Pages
- 3240-3249
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5669553
- OpenAlex
- W2750718695
- Semantic Scholar
- ef022dba477c27d3e9b6fce59a1f5267296be580
- Cited by
- 911
- References
- 162
- Citations by year
- 2026: 64 · 2025: 98 · 2024: 109 · 2023: 105 · 2022: 134 · 2021: 127 · 2020: 148 · 2019: 66 · 2018: 52 · 2017: 7
- FWCI
- 7.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- DZNE Pub (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, Alzheimer's disease, microglial activation, neuroinflammation, phagocytosis, neuroprotection, microglial receptors, neurodegeneration, brain homeostasis
- MeSH terms
- Alzheimer Disease, Animals, Brain, Central Nervous System, Complement System Proteins, Humans, Immune System, Inflammation, Macrophages, Phagocytosis, Cytokines, Microglia, Neurodegenerative Diseases, Cell Proliferation, Toll-Like Receptors, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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