IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline

Fu, Amy K. Y.; Hung, Kwok-Wang; Yuen, Michael Y. F.; Zhou, Xiaopu; Mak, Deejay S. Y.; Chan, Ivy C. W.; Cheung, Tom H.; Zhang, Baorong; Fu, Wing-Yu; Liew, Foo Y.; Ip, Nancy Y.

doi:10.1073/pnas.1604032113

Cited by 371Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsIL-33, ST2, and ILC Pathways

IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline

Open access

Fu, Amy K. Y., Hung, Kwok-Wang, Yuen, Michael Y. F., Zhou, Xiaopu, Mak, Deejay S. Y., Chan, Ivy C. W., Cheung, Tom H., Zhang, Baorong +3 more·2016·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1604032113PMC PMC4868478

Open this paper in CoChat — free account Open PDF

Abstract

Significance: Dysfunction of the innate immune system is involved in the pathogenesis of Alzheimer’s disease (AD); however, the pathophysiological mechanisms underlying these dysfunctions are unclear. Here we report that stimulation of IL-33/ST2 signaling rescues memory deficits and reduces the accumulation of β-amyloid in APP/PS1 mice that exhibit select pathologies associated with AD. Although impaired IL-33/ST2 signaling is associated with early progression of AD, IL-33 injection rescues contextual memory deficits and reduces the accumulation of β-amyloid in APP/PS1 mice. IL-33 skews the microglia toward an alternative activation state with enhanced Aβ phagocytic capacity and elevated antiinflammatory gene expression, which results in a decreased proinflammatory response in the brain. Thus, this study suggests that IL-33 can be developed as a new therapeutic intervention for AD.

AI snapshot

Written from the paper’s full text.

TL;DR

IL-33 administration reversed synaptic plasticity and contextual memory deficits and reduced amyloid pathology in APP/PS1 mice by enhancing microglial Aβ phagocytosis and shifting microglia/macrophages toward an antiinflammatory phenotype. The findings support IL-33/ST2 signaling as a potential therapeutic target in Alzheimer’s disease.

Key findings

In 6- to 7-mo-old APP/PS1 mice, i.p. IL-33 (200 ng for 2 d) dramatically reversed impaired hippocampal LTP and restored contextual fear memory at 7 d after shock.
IL-33 reduced soluble Aβ in cortices of 10-mo-old APP/PS1 mice by 54 ± 9% (n = 3 experiments); soluble Aβx-40 and Aβx-42 decreased by ∼50% and ∼30%, respectively. It also reduced 4G8-stained amyloid plaques in 12-mo-old APP/PS1 mice, and intracerebroventricular sST2 abolished this plaque reduction.
IL-33 increased Aβ phagocytosis: methoxy-X04-labeled Aβ was detected in ∼33% of CD11b+ myeloid cells from APP/PS1 cortices, rising to ∼47% after IL-33; Aβ uptake by resident microglia increased by ∼80%, while infiltrating monocytes remained relatively stable.
IL-33 increased antiinflammatory Arg1 and Fizz1 mRNA in CD11b+ myeloid cells and suppressed proinflammatory IL-1β, IL-6, and NLRP3 in APP/PS1 cortices; ST2-deficient microglia abolished IL-33-stimulated Aβ uptake.

Methods

Mouse models: APP/PS1, 5XFAD, and St2−/− mice; WT C57BL/6 controls. In vivo IL-33 was given i.p. at 200 ng per mouse for 2 consecutive days, with some experiments using intracerebroventricular sST2 via osmotic pumps.
Outcomes included hippocampal LTP at SC-CA1 synapses, open field habituation, contextual fear conditioning, soluble/insoluble Aβ by Western blot and ELISA, 4G8 plaque immunohistochemistry, microglial Aβ phagocytosis by flow cytometry, and inflammatory gene expression by ddPCR/qRT-PCR.
Human data: serum sST2 measured in 17 healthy controls and 18 patients with MCI (Han Chinese, age ≥60 y), with clinical diagnosis by NINCDS-ADRDA criteria.

Limitations

The paper does not include a dedicated limitations section; it states that whether IL-33/ST2 suppression of proinflammatory gene production via MyD88 competition mediates the observed effects “awaits further study,” and that further phenotypic characterization of the microglial subset with increased Aβ phagocytic capacity is needed.
Evident from the text: the therapeutic evidence is primarily from transgenic mouse models, and the human data are limited to cross-sectional serum sST2 in small groups (17 controls, 18 MCI), not IL-33 treatment or clinical outcomes.
Evident from the text: long-term safety, dosing durability, and whether the murine findings extrapolate to human AD are not established.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1073/pnas.1604032113

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 5 cited sources checked · 0 supported · 0 flagged

Findingown data
IL-33 injection increases the proportion of CD11b+ cells exhibiting methoxy-X04 fluorescence to approximately 47% in APP/PS1 mice.
“IL-33 injection further increased the proportion of CD11b + cells exhibiting methoxy-X04 fluorescence (∼47%; Fig. 3 F and G).”
Quote in the paperSubstantial claim
Findingown data
IL-33 administration significantly increases Aβ phagocytic uptake by resident microglia by approximately 80% in APP/PS1 mice.
“IL-33 administration significantly increased Aβ phagocytic uptake by resident microglia by ∼80%, whereas the percentage of Aβ-containing infiltrating monocytes remained relatively stable (Fig. 3 H and I and SI Appendix, Fig. S8 E-G).”
Quote in the paperSubstantial claim
Findingown data
IL-33 administration reduces soluble Aβ x-40 and Aβ x-42 species in the cortices of 10-mo-old APP/PS1 mice.
“Specifically, soluble Aβ x-40 and Aβ x-42 species, which play major synaptotoxic roles in AD (21), were decreased by ∼50% and ∼30%, respectively, in the cortices of 10-mo-old IL-33-administered APP/PS1 mice (Fig. 2B).”
Quote in the paperSubstantial claim
Findingown data
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
IL-33 administration reduces soluble Aβ levels in the cortices of APP/PS1 mice.
“IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation.”
Quote in the paperSubstantial claim
Findingown data
IL-33 administration increases CD68 expression in Iba1+ myeloid cells in close contact with amyloid plaques in APP/PS1 mice.
“IL-33 administration increased CD68 expression in Iba1 + myeloid cells, that were in close contact with amyloid plaques (Fig. 3E).”
Quote in the paperSubstantial claim

Findingown data
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
Serum levels of soluble ST2 (sST2) are significantly higher in patients with mild cognitive impairment (MCI) than in healthy controls.
“Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD.”
- Also stated in: § Results · plain
  “We found significantly higher levels of serum sST2, a decoy receptor of IL-33, in patients with mild cognitive impairment (MCI; with an increased risk of developing to AD in later life) compared with healthy controls (Fig. 1A);”
Quote in the paperSubstantial claim
Findingown data
IL-33 treatment increases the colocalization of myeloid cells and amyloid plaques in APP/PS1 mouse brains.
“Our 3D analysis confirmed the increased colocalization of myeloid cells and amyloid plaques in IL-33treated APP/PS1 mouse brains (Fig. 3 B and C), supporting the notion that IL-33 enhances the proximity between myeloid cells and amyloid plaques.”
Quote in the paperSubstantial claim
Findingown data
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
IL-33 administration reverses synaptic plasticity impairment in APP/PS1 mice.
“Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice.”
- Also stated in: § Results · boosted
  “An i.p. injection of recombinant IL-33 (200 ng) for 2 d dramatically reversed the LTP impairment of APP/PS1 mice (Fig. 1 B and C).”
Quote in the paperSubstantial claim
Findingown data
IL-33 injection enhances the recruitment of Iba1+ myeloid cells to amyloid plaques in the cortices of APP/PS1 mice.
“IL-33 injection enhanced the recruitment of Iba1 + myeloid cells to amyloid plaques in these cortices (Fig. 3A).”
Quote in the paperSubstantial claim
Findingown data
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
IL-33 administration reverses memory deficits in APP/PS1 mice.
“Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice.”
- Also stated in: § Results · plain
  “IL-33 treatment was able to restore the impaired freezing response of the APP/PS1 mice at 7 d after the electric shock (Fig. 1G).”
- Also stated in: § Results · boosted
  “Collectively, these results demonstrate that IL-33 can rescue the synaptic dysfunction and memory deficits of APP/PS1 mice.”
Quote in the paperSubstantial claim
Findingown data
Methoxy-X04-labeled Aβ is detected in approximately 33% of CD11b+ myeloid cells from the cortices of APP/PS1 mice.
“Flow cytometry analysis detected methoxy-X04-labeled Aβ in ∼33% of the CD11b + myeloid cells from the cortices of the APP/PS1 mice (Fig. 3 F and G), but not those of WT mice (SI Appendix, Fig. S7).”
Quote in the paperSubstantial claim
Findingown data
IL-33 administration reduces 4G8-stained amyloid plaques in 5XFAD mice.
“IL-33 administration for 2 d also reduced 4G8-stained amyloid plaques in 5XFAD mice, another AD transgenic mouse model (SI Appendix, Fig. S6).”
Quote in the paperSubstantial claim
Findingown data
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
IL-33 administration reduces amyloid plaque deposition in APP/PS1 mice.
“IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation.”
- Also stated in: § Results · plain
  “At 2 d after IL-33 treatment, the 4G8-labeled amyloid plaques were significantly reduced in the cortices of 12-mo-old APP/PS1 mice (Fig. 2 C and D).”
Quote in the paperSubstantial claim
Findingown data
APP/PS1 mice exhibit approximately 3.6-fold more infiltrating monocytes (CD11b+ CD45hi myeloid cells) than WT mice.
“The APP/PS1 mice exhibited ∼3.6-fold more infiltrating mono- cytes (CD11b + CD45 hi myeloid cells) compared with the WT mice (SI Appendix, Fig. S8 A-D).”
Quote in the paperSubstantial claim
Findingown data
Intracerebroventricular administration of sST2 abolishes the IL-33-mediated reduction of 4G8-stained amyloid plaques in APP/PS1 mice.
“Importantly, intracerebroventricular administration of sST2 abolished the IL-33-mediated reduction of 4G8-stained amyloid plaques in the APP/PS1 mice (Fig. 2 C and D), demonstrating the specificity and the central activation of myeloid cells of IL-33/ST2 signaling in ameliorating the cerebral amyloid pathology.”
Quote in the paperSubstantial claim
Findingown data
In APP/PS1 mice, approximately 80% of CD11b+ CD45hi infiltrating monocytes take up methoxy-X04-labeled Aβ.
“In the APP/PS1 mice, ∼10% of CD11b + CD45 lo resident microglia phagocytosed Aβ (Fig. 3 H and I), and ∼80% of CD11b + CD45 hi infiltrating monocytes took up the methoxy-X04-labeled Aβ (SI Appendix, Fig. S8 E-G).”
Quote in the paperNot a substantial claim
Findingown data
In APP/PS1 mice, approximately 10% of CD11b+ CD45lo resident microglia phagocytose Aβ.
“In the APP/PS1 mice, ∼10% of CD11b + CD45 lo resident microglia phagocytosed Aβ (Fig. 3 H and I), and ∼80% of CD11b + CD45 hi infiltrating monocytes took up the methoxy-X04-labeled Aβ (SI Appendix, Fig. S8 E-G).”
Quote in the paperSubstantial claim
Findingown data
Serum sST2 levels differ significantly between healthy control subjects (n = 17) and patients with MCI (n = 18).
“Boxplot showing the sST2 levels in the serum of healthy subjects (NC; n = 17) and patients with MCI (n = 18).*P < 0.05, two-sample t test.”
Quote in the paperNot a substantial claim
Findingown data
IL-33 enhances the uptake of fluorescence-labeled oligomeric Aβ1-42 in cultured microglial cells from WT mice in a dose-dependent manner.
“IL-33 enhanced the uptake of fluorescence-labeled oligomeric Aβ 1-42 in cultured microglial cells in WT mice in a dose-dependent manner (SI Appendix, Fig. S10), but not in ST2-deficient microglia (Fig. 4C).”
Quote in the paperSubstantial claim
Findingown data
ST2-deficient microglia abolish IL-33-stimulated Aβ uptake.
“(C) ST2-deficient microglia abolished the IL-33stimulated Aβ uptake.”
Quote in the paperSubstantial claim
Findingown data
IL-33 increases the percentage of CD11b+ mononuclear cells containing methoxy-X04-labeled Aβ in APP/PS1 mouse brains at 17 months of age.
“Representative scatterplots and quantification show the percentages of CD11b + mononuclear cells (F and G) and CD11b + CD45 lo cells (H and I) containing methoxy-X04-labeled Aβ in the APP/PS1 mouse brains (17 mo old) after IL-33 administration.”
Quote in the paperSubstantial claim
Findingown data
IL-33 increases CD68 expression in Aβ plaques.
“(D and E) IL-33 increases CD68 expression in Aβ plaques.”
Quote in the paperSubstantial claim
Findingown data
IL-33 administration increases neprilysin protein level in the brains of APP/PS1 mice at 14 months of age.
“(A and B) IL-33 administration increases neprilysin protein level in the brains of APP/PS1 mice.”
Quote in the paperSubstantial claim
Findingown data
APP/PS1 mice exhibit significantly slower habituation to the testing environment than WT mice.
“The APP/PS1 mice exhibited significantly slower habituation to the testing environment than the WT mice; however, the IL-33-treated APP/PS1 mice showed significantly improved habituation to the testing environment (Fig. 1D and SI Appendix, Fig. S1).”
Quote in the paperSubstantial claim
Findingown data
In APP/PS1 mice, proinflammatory genes including IL-1β, IL-6, and NLRP3 are significantly induced in the brain cortex.
“In the APP/PS1 mice, proinflammatory genes including IL-1β, IL-6, and NLRP3 (NOD-like receptor family, pyrin domain-containing 3, a key component in the inflammasome cascade) were significantly induced in the brain cortex.”
Quote in the paperSubstantial claim
Findingown data
IL-33 increases the percentage of CD11b+CD45lo cells containing methoxy-X04-labeled Aβ in APP/PS1 mouse brains at 17 months of age.
“Representative scatterplots and quantification show the percentages of CD11b + mononuclear cells (F and G) and CD11b + CD45 lo cells (H and I) containing methoxy-X04-labeled Aβ in the APP/PS1 mouse brains (17 mo old) after IL-33 administration.”
Quote in the paperSubstantial claim
Findingcitation
LTP is significantly impaired in 6- to 7-mo-old APP/PS1 mice.
“Whereas high-frequency stimulation significantly increased the magnitude of long-term potentiation (LTP) at Schaffer collateral (SC)-CA1 synapses in the hippocampus of wild type (WT) mice, LTP was significantly impaired in 6-to 7-mo-old APP/PS1 mice (17,18).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [17] source
  Not checked in the free run.
- cites [18] source
  Not checked in the free run.
Findingown data
IL-33 administration reduces Aβ plaques in APP/PS1 mice.
“IL-33 administration reduces soluble Aβ levels and Aβ plaques in APP/PS1 mice.”
- Also stated in: § Statistical Analysis. · plain
  “(C and D) IL-33 ameliorated amyloid plaque pathology in APP/PS1 mice.”
Quote in the paperSubstantial claim
Findingown data
IL-33 treatment restores the impaired freezing response of APP/PS1 mice at 7 d after electric shock.
“Whereas the IL-33-treated APP/PS1 mice did not exhibit an improvement in freezing performance 1 d after the electric shock (Fig. 1F), IL-33 treatment was able to restore the impaired freezing response of the APP/PS1 mice at 7 d after the electric shock (Fig. 1G).”
Quote in the paperSubstantial claim
Findingown data
IL-33 administration increases mRNA expression of Arg1 and Fizz1 in CD11b+ myeloid cells isolated from both WT and APP/PS1 mouse brains.
“Importantly, the mRNA expression of Arg1 and Fizz1, which are associated with antiinflammatory action, was significantly increased in CD11b + myeloid cells isolated from both WT and APP/PS1 mouse brains after IL-33 administration (Fig. 4 D and E).”
Quote in the paperSubstantial claim
Findingown data
IL-33-treated APP/PS1 mice do not exhibit improvement in freezing performance 1 d after electric shock.
“Whereas the IL-33-treated APP/PS1 mice did not exhibit an improvement in freezing performance 1 d after the electric shock (Fig. 1F), IL-33 treatment was able to restore the impaired freezing response of the APP/PS1 mice at 7 d after the electric shock (Fig. 1G).”
Quote in the paperNot a substantial claim
Findingown data
IL-33 increases the colocalization of Iba1+ myeloid cells and Aβ plaques in the cortices of APP/PS1 mice at 12 months of age.
“(A-C) IL-33 increases the colocalization of Iba1 + myeloid cells and Aβ plaques in the cortices of APP/PS1 mice (12 mo old).”
Quote in the paperSubstantial claim
Findingown data
IL-33 administration reduces soluble Aβ levels in APP/PS1 mice.
“IL-33 administration reduces soluble Aβ levels and Aβ plaques in APP/PS1 mice.”
- Also stated in: § Statistical Analysis. · plain
  “(A) IL-33 reduced soluble Aβ content.”
Quote in the paperSubstantial claim
Findingown data
IL-33-treated APP/PS1 mice show significantly improved habituation to the testing environment.
“The APP/PS1 mice exhibited significantly slower habituation to the testing environment than the WT mice; however, the IL-33-treated APP/PS1 mice showed significantly improved habituation to the testing environment (Fig. 1D and SI Appendix, Fig. S1).”
Quote in the paperSubstantial claim
Findingown data
IL-33 administration significantly suppresses the increased expression of proinflammatory genes IL-1β, IL-6, and NLRP3 in the brain cortex of APP/PS1 mice.
“IL-33 administration significantly suppressed the increased expression of these proinflammatory genes (Fig. 4 F-H).”
Quote in the paperSubstantial claim
Findingown data
IL-33 administration does not significantly change the percentage of Aβ-containing infiltrating monocytes in APP/PS1 mice.
“IL-33 administration significantly increased Aβ phagocytic uptake by resident microglia by ∼80%, whereas the percentage of Aβ-containing infiltrating monocytes remained relatively stable (Fig. 3 H and I and SI Appendix, Fig. S8 E-G).”
Quote in the paperNot a substantial claim
Findingown data
ST2 downstream signaling molecules p38 and ERK1/2 MAPKs are activated in cultured microglia on IL-33 treatment.
“Concordant with the prominent expression of ST2 in microglia (SI Appendix, Fig. S11A), the downstream signaling molecules (p38 and ERK1/2 MAPKs) of ST2 receptors were activated in cultured microglia on IL-33 treatment (SI Appendix, Fig. S11 B-D).”
Quote in the paperSubstantial claim
Findingown data
IL-33 reaches the brain within 30 min after i.p. injection.
“IL-33 reached the brain within 30 min after i.p. injection (SI Appendix, Fig. S3), consistent with earlier findings of a compromised blood-brain barrier in both APP/PS1 mice and patients with AD (19,20).”
Quote in the paperSubstantial claim
Findingown data
APP/PS1 mice exhibit reduced freezing behavior at 1 d and 7 d after electric shock, indicating impaired contextual retrieval of fear memory.
“Compared with the WT mice, the APP/PS1 mice exhibited reduced freezing behavior at 1 d and 7 d after the electric shock, indicating an impaired contextual retrieval of fear memory (Fig. 1 F and G).”
Quote in the paperSubstantial claim
Findingown data
IL-33-treated APP/PS1 mice at 14 months of age exhibit improved habituation in the exploratory open field test.
“(D) IL-33-treated APP/PS1 mice (14 mo old) exhibit improved habituation in the exploratory open field (OF) test.”
Quote in the paperSubstantial claim
Findingown data
IL-33 does not enhance the uptake of fluorescence-labeled oligomeric Aβ1-42 in ST2-deficient microglia.
“IL-33 enhanced the uptake of fluorescence-labeled oligomeric Aβ 1-42 in cultured microglial cells in WT mice in a dose-dependent manner (SI Appendix, Fig. S10), but not in ST2-deficient microglia (Fig. 4C).”
Quote in the paperSubstantial claim
Findingown data
sST2 is increased in the serum of patients with MCI.
“IL-33 expression is reduced in the brains of patients with AD (15), and sST2 is increased in the serum of patients with MCI, as demonstrated in the present study (Fig. 1A).”
Quote in the paperSubstantial claim
Findingown data
APP/PS1 mutant mice at 6 to 7 months of age exhibit impaired LTP in the hippocampal CA1 region.
“IL-33 rescues LTP impairment in APP/PS1 mutant mice.”
Quote in the paperSubstantial claim
Interpretationreasoning
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
Impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD.
“Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD.”
Quote in the paperSubstantial claim
- Rests on an assumption: The mechanisms underlying the onset and progression of AD remain unclear.
Interpretationown data
IL-33/ST2 signaling in myeloid cells specifically mediates the amelioration of cerebral amyloid pathology.
“Importantly, intracerebroventricular administration of sST2 abolished the IL-33-mediated reduction of 4G8-stained amyloid plaques in the APP/PS1 mice (Fig. 2 C and D), demonstrating the specificity and the central activation of myeloid cells of IL-33/ST2 signaling in ameliorating the cerebral amyloid pathology.”
Quote in the paperSubstantial claim
Interpretationown data
IL-33 administration increases phagocytic Aβ uptake by myeloid cells.
“These findings suggest that IL-33 administration increases phagocytic Aβ uptake by myeloid cells.”
Quote in the paperSubstantial claim
Interpretationown data
Peripheral IL-33 administration in AD mouse models alleviates AD-like pathology by enhancing microglial phagocytosis and degradation of Aβ.
“The present study demonstrates that peripheral IL-33 administration in AD mouse models alleviates AD-like pathology by enhancing microglial phagocytosis and degradation of Aβ.”
Quote in the paperSubstantial claim
Interpretationown data
IL-33 regulates inflammatory responses in the APP/PS1 mouse brain.
“Taken together, these findings suggest that IL-33 regulates inflammatory responses in the APP/PS1 mouse brain.”
Quote in the paperSubstantial claim
Interpretationown data
IL-33 enhances the proximity between myeloid cells and amyloid plaques.
“Our 3D analysis confirmed the increased colocalization of myeloid cells and amyloid plaques in IL-33treated APP/PS1 mouse brains (Fig. 3 B and C), supporting the notion that IL-33 enhances the proximity between myeloid cells and amyloid plaques.”
Quote in the paperSubstantial claim
Interpretationown data
IL-33 drives microglia/macrophages in APP/PS1 mouse brains toward an alternative activation phenotype.
“These results suggest that IL-33 drives the microglia/macrophages in the APP/PS1 mouse brains toward an alternative activation phenotype, which may contribute to neuroprotective functions.”
- Also stated in: § Discussion · hedged
  “Indeed, we show that IL-33 administration causes an increase in the antiinflammatory genes Arg1 and Fizz1 in microglia/macrophages in the brain, suggesting that IL-33 enhances the polarization of microglia/ macrophages to an alternative activation phenotype.”
Quote in the paperSubstantial claim
Interpretationreasoning
IL-33 administration can be developed as a potential therapeutic intervention for AD.
“Considered along with the beneficial effects of IL-33 on synaptic and memory functions in the AD-like mouse model, our results suggest that IL-33 administration can be developed as a potential therapeutic intervention for AD.”
Quote in the paperSubstantial claim
- Rests on an assumption: There is no effective therapy for AD.
- Rests on an assumption: The mechanisms underlying the onset and progression of AD remain unclear.
Interpretationown data
IL-33-dependent activation of ST2 signaling in microglia enhances Aβ phagocytosis and clearance.
“These findings suggest that IL-33-dependent activation of ST2 signaling in microglia enhances Aβ phagocytosis and clearance.”
Quote in the paperSubstantial claim
Interpretationown data
The increase of neprilysin protein in the brains of APP/PS1 mice after IL-33 administration provides insight into the mechanism of enzymatic degradation of Aβ in the IL-33-treated condition.
“The increase of neprilysin protein in the brains of APP/PS1 mice after IL-33 administration (Fig. 4 A and B) provides insight into the mechanism of the enzymatic degradation of Aβ in the IL-33-treated condition.”
Quote in the paperSubstantial claim
Interpretationown data
IL-33 drives microglia to an alternative activation state in APP/PS1 mice.
“(D and E) IL-33 drives microglia to an alternative activation state in APP/PS1 mice.”
Quote in the paperSubstantial claim
Interpretationown data
ST2 signaling in microglia mediates the IL-33-associated enhancement of Aβ phagocytosis in the brain of APP/PS1 mice.
“These results indicate that ST2 signaling in microglia mediates the IL-33-associated enhancement of Aβ phagocytosis in the brain of APP/PS1 mice.”
Quote in the paperSubstantial claim
Interpretationown data
IL-33 administration enhances microglial phagocytosis of Aβ.
“IL-33 administration enhances microglial phagocytosis of Aβ.”
- Also stated in: § Statistical Analysis. · plain
  “(F-I) IL-33 enhances the phagocytic activity of resident microglial cells.”
Quote in the paperSubstantial claim
Premisecitation
IL-33 expression is reduced in the brains of patients with AD.
“IL-33 expression is reduced in the brains of patients with AD (15), and sST2 is increased in the serum of patients with MCI, as demonstrated in the present study (Fig. 1A).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [15] source
  Not checked in the free run.
Interpretationcitation
Observations in the murine AD model could be extrapolated to humans.
“Indeed, genetic studies have linked IL-33/ST2 single nucleotide polymorphisms to clinical AD (15,51), suggesting that our observations in the murine AD model could be extrapolated to humans.”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [15] source
  Not checked in the free run.
- cites [51] source
  Not checked in the free run.
Interpretationown data
IL-33 modulates inflammatory responses in APP/PS1 mice.
“IL-33 modulates inflammatory responses in APP/PS1 mice.”
Quote in the paperSubstantial claim
Interpretationown data
IL-33 specifically enhances Aβ uptake by microglia.
“IL-33 specifically enhances Aβ uptake by microglia.”
Quote in the paperSubstantial claim
Interpretationown data
IL-33 mobilizes innate immunity to prevent and clear established Aβ accumulation even at late stages of the disease.
“Our finding that IL-33 mobilizes innate immunity to prevent and clear established Aβ accumulation even at late stages of the disease represents a new treatment paradigm for AD.”
Quote in the paperSubstantial claim

The quote only partly states this claim. 3
May combine two claims. 6
Classified as probably not a substantial claim. 2

The quote only partly states this claim.
Findingown data
IL-33 administration rescues LTP impairment in APP/PS1 mutant mice at 6 to 7 months of age in the hippocampal CA1 region.
“IL-33 rescues LTP impairment in APP/PS1 mutant mice.”
Quote in the paperSubstantial claim
The quote only partly states this claim.
Findingown data
IL-33 ameliorates memory retrieval deficits of APP/PS1 mice in fear conditioning tests at 1 day after electric shock.
“IL-33 ameliorates memory retrieval deficits of APP/PS1 mice in fear conditioning (FC) tests.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
At the concentration used (200 ng i.p. daily for 2 d), IL-33 does not affect general health or plasma histamine level in WT or APP/PS1 mice.
“At the concentration used (200 ng i.p. daily for 2 d), IL-33 did not affect the general health or plasma histamine level in either WT or APP/PS1 mice (SI Appendix, Fig. S4).”
Quote in the paperNot a substantial claim
The quote only partly states this claim.
Findingown data
IL-33 ameliorates memory retrieval deficits of APP/PS1 mice in fear conditioning tests at 7 days after electric shock.
“IL-33 ameliorates memory retrieval deficits of APP/PS1 mice in fear conditioning (FC) tests.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
IL-33 administration mitigates amyloid plaque pathology in APP/PS1 mice through enhancement of Aβ phagocytosis by resident microglia and Aβ clearance, probably by increasing neprilysin levels.
“Taken together, our results demonstrate that IL-33 administration mitigates the amyloid plaque pathology in APP/PS1 mice through the enhancement of Aβ phagocytosis by resident microglia and Aβ clearance, probably by increasing neprilysin levels.”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim.
Study design and conductnone given
Investigators who performed the electrophysiological, immunohistochemical, RNA expression, and flow cytometry analyses and the behavioral tests were blinded to the genotypes of the mice and treatment conditions.
“The investigators who performed the electrophysiological, immunohistochemical, RNA expression, and flow cytometry analyses and the behavioral tests were blinded to the genotypes of the mice and treatment conditions.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
IL-33 administration ameliorates synaptic impairment and behavioral deficits in APP/PS1 mice.
“IL-33 administration ameliorates synaptic impairment and behavioral deficits in APP/PS1 mice.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
IL-33 treatment reverses contextual memory deficits in APP/PS1 mice, probably through ameliorating hippocampal synaptic dysfunctions.
“These data suggest that IL-33 treatment reverses contextual memory deficits in APP/PS1 mice, probably through ameliorating the hippocampal synaptic dysfunctions.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
IL-33 administration reduces soluble Aβ levels and Aβ plaques in APP/PS1 mice.
“IL-33 administration reduces soluble Aβ levels and Aβ plaques in APP/PS1 mice.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data
The purity of microglia/infiltrating monocyte isolation was routinely greater than 90%, as determined by fluorescence staining for CD11b and flow cytometry analysis.
“The purity of microglia/infiltrating monocyte isolation was routinely >90% as determined by fluorescence staining for CD11b and flow cytometry analysis.”
Quote in the paperNot a substantial claim
May combine two claims.
Interpretationown data
IL-33 treatment switches microglia/macrophages to an alternative activation phenotype, resulting in a reduction of the proinflammatory response in AD mouse brains.
“Furthermore, IL-33 treatment switches the microglia/macrophages to an alternative activation phenotype, resulting in a reduction of the proinflammatory response in the AD mouse brains.”
Quote in the paperSubstantial claim

11 of 11

The paper relies on this without support.
There is no effective therapy for AD.
“There is no effective therapy for AD, in part because of our limited knowledge of its underlying pathophysiological mechanisms.”
The paper relies on this without support.
The mechanisms underlying the onset and progression of AD remain unclear.
“The mechanisms underlying the onset and progression of AD remain unclear.”

2 of 2

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?

The authors' results support previous studies showing improved behaviour in AD mouse models associated with enhanced microglial amyloid plaque phagocytosis in response to scanning ultrasound and treatment with IL-33.
“Our results support previous studies showing improved behaviour in AD mouse models associated with enhanced microglial amyloid plaque phagocytosis in response to scanning ultrasound69, and treatment with IL-33 that signals exclusively via MyD8870.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [70]
The paper reports that IL-33 treatment reverses cognitive deficits in APP/PS1 mice and enhances microglial Aβ phagocytosis (introductory summary and Results, Fig. 3). Its Discussion says ST2 activation recruits MyD88, but does not establish that IL-33 signals exclusively through MyD88. The scanning-ultrasound finding is attached to a different citation and is not assessed here. (LLM, conf=0.86)
Experimental — accuracy not yet measured
CD45 is differentially expressed on microglia (CD45lo/CD11b+) and recruited myeloid cells (CD45hi/CD11b+), and this distinction is commonly used in flow cytometry to distinguish recruited myeloid cells from resident microglia in various disease states.
“CD45 is differentially expressed on microglia (CD45lo/CD11b+) and recruited myeloid cells (CD45hi/CD11b+), and this distinction is commonly used in flow cytometry experiments to distinguish recruited myeloid cells from resident microglia in various disease states [27, 40, 41].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [27]
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 measured
IL-33 administration ameliorated memory deficits and reduced Aβ deposition in the APP/PS1 mouse model.
“Furthermore, IL-33 administration ameliorated memory deficits and reduced Aβ deposition in the APP/PS1 mouse model (54).”
From The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies (2023) · cites this paper as [54]
Activation of microglial cells by inflammatory molecules has been shown to enhance Aβ clearance by microglia.
“Strikingly, activation of microglial cells by inflammatory molecules has been shown to enhance Aβ clearance by microglia [3, 26, 27].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [27]
IL-33 ameliorated AD-associated phenotypes by promoting anti-inflammatory functions, which included induction of Arg1.
“IL-33 ameliorated AD-associated phenotypes by promoting anti-inflammatory functions, which included induction of Arg1 (80).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [80]

Clinical diagnosis of Alzheimer's disease: Report of the NINCDS‐ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226 · see citing works
2016 Alzheimer's disease facts and figures
Alzheimer's Association (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.03.001 · Cited by 5,069 · see citing works
IL-33, an Interleukin-1-like Cytokine that Signals via the IL-1 Receptor-Related Protein ST2 and Induces T Helper Type 2-Associated Cytokines
Schmitz, J., Owyang, A. M., Oldham, E. R., Song, Y., Murphy, E., McClanahan, T. K., Zurawski, G., Moshrefi, M., Qin, J., Li, X., et al. (2005) · Immunity · doi:10.1016/j.immuni.2005.09.015 · Cited by 3,701 · see citing works
Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · cited 1× · see citing works
“The generation of 5XFAD mice overexpressing the K670N/M671L (Swedish), I716V (Florida), and V717I (London) mutations in human APP (695), as well as M146L and L286V mutations in human PS1, has been described previously (53).”
Background
NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice
Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., et al. (2013) · Nature · doi:10.1038/nature11729 · Cited by 2,898 · see citing works
Immune attack: the role of inflammation in Alzheimer disease
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3880 · Cited by 2,134 · see citing works
Blood-brain barrier breakdown in the aging human hippocampus
Montagne, A., Barnes, S. R., Sweeney, M. D., Halliday, M. R., Sagare, A. P., Zhao, Z., Toga, A. W., Jacobs, R. E., Liu, C. Y., Amezcua, L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.032 · Cited by 2,102 · see citing works
Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078 · see citing works
New tools for studying microglia in the mouse and human CNS
Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525528113 · Cited by 1,804 · see citing works
The history of toll-like receptors - redefining innate immunity
O'Neill, L. A. J., Golenbock, D., & Bowie, A. G. (2013) · Nature reviews. Immunology · doi:10.1038/nri3446 · Cited by 1,765 · see citing works
TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736 · see citing works
2015 Alzheimer's disease facts and figures
Alzheimer's Association (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.02.003 · Cited by 1,641 · see citing works
Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase
Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575 · see citing works
CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer
Stewart, C. R., Stuart, L. M., Wilkinson, K., van Gils, J. M., Deng, J., Halle, A., Rayner, K. J., Boyer, L., Zhong, R., Frazier, W. A., et al. (2010) · Nature Immunology · doi:10.1038/ni.1836 · Cited by 1,513 · see citing works
Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice
Hickman, S. E., Allison, E. K., & El Khoury, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0616-08.2008 · Cited by 1,329 · cited 1× · see citing works
“Interestingly, the Aβ-clearing capacity of microglia in APP/PS1 mice is impaired with aging, as revealed by reduced expression of Aβ-binding receptors and Aβdegrading enzymes (37).”
Background
Disease-associated functions of IL-33: the new kid in the IL-1 family
Liew, F. Y., Pitman, N. I., & McInnes, I. B. (2010) · Nature reviews. Immunology · doi:10.1038/nri2692 · Cited by 1,004 · see citing works
Self-citation
Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction
Mucke, L., & Selkoe, D. J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006338 · Cited by 1,000 · see citing works
The Genetics of Alzheimer's Disease
Bertram, L., & Tanzi, R. E. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00008-4 · Cited by 784 · see citing works
The genetics of Alzheimer disease
Tanzi, R. E. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006296 · Cited by 727 · see citing works
Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease
Jacobsen, J. S., Wu, C.-C., Redwine, J. M., Comery, T. A., Arias, R., Bowlby, M., Martone, R., Morrison, J. H., Pangalos, M. N., Reinhart, P. H., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600948103 · Cited by 701 · see citing works
DT‐01‐04: The efficacy of RVT‐101, a 5‐ht6 receptor antagonist, as an adjunct to donepezil in adults with mild‐to‐moderate Alzheimer's disease: Completer analysis of a phase 2b study
Lombardo, I., Ramaswamy, G., Piscitelli, S. C., & Friedhoff, L. T. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.08.154 · Cited by 656 · see citing works
IL-33 reduces the development of atherosclerosis
Miller, A. M., Xu, D., Asquith, D. L., Denby, L., Li, Y., Sattar, N. A., Baker, A. H., McInnes, I. B., & Liew, F. Y. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071868 · Cited by 642 · see citing works
Self-citation
Interleukin-33 in tissue homeostasis, injury, and inflammation
Molofsky, A. B., Savage, A. K., & Locksley, R. M. (2015) · Immunity · doi:10.1016/j.immuni.2015.06.006 · Cited by 638 · see citing works
ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance
Brint, E. K., Xu, D., Liu, H., Dunne, A., McKenzie, A. N. J., O'Neill, L. A. J., & Liew, F. Y. (2004) · Nature Immunology · doi:10.1038/ni1050 · Cited by 489 · see citing works
Self-citation
IL-33 exacerbates antigen-induced arthritis by activating mast cells
Xu, D., Jiang, H., Kewin, P., Li, Y., Mu, R., Fraser, A. R., Pitman, N. I., Kurowska‐Stolarska, M., McKenzie, A. N. J., McInnes, I. B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801898105 · Cited by 465 · see citing works
Self-citation
Immune surveillance in the central nervous system
Ousman, S. S., & Kubes, P. (2012) · Nature Neuroscience · doi:10.1038/nn.3161 · Cited by 433 · see citing works
Innate immunity in diabetes and diabetic nephropathy
Wada, J., & Makino, H. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.175 · Cited by 432 · see citing works
Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease–like pathology and cognitive decline
vom Berg, J., Prokop, S., Miller, K. R., Obst, J., Kälin, R. E., Lopategui-Cabezas, I., Wegner, A., Mair, F., Schipke, C. G., Peters, O., et al. (2012) · Nature Medicine · doi:10.1038/nm.2965 · Cited by 416 · see citing works
Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death
Neher, J. J., Neniskyte, U., Zhao, J.-W., Bal-Price, A., Tolkovsky, A. M., & Brown, G. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003600 · Cited by 373 · see citing works
Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology
Guillot-Sestier, M.-V., Doty, K. R., Gate, D., Rodriguez, J., Leung, B. P., Rezai-Zadeh, K., & Town, T. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.068 · Cited by 363 · see citing works
The Glia-Derived Alarmin IL-33 Orchestrates the Immune Response and Promotes Recovery following CNS Injury
Gadani, S. P., Walsh, J. T., Smirnov, I., Zheng, J., & Kipnis, J. (2015) · Neuron · doi:10.1016/j.neuron.2015.01.013 · Cited by 359 · see citing works
IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior
Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J. A., Funk, C. C., Moore, B., DiNunno, N., Rosario, A. M., Cruz, P. E., Verbeeck, C., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.11.020 · Cited by 354 · see citing works
Dealing with danger in the CNS: the response of the immune system to injury
Gadani, S. P., Walsh, J. T., Lukens, J. R., & Kipnis, J. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.019 · Cited by 342 · see citing works
Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity
Gomez-Nicola, D., & Perry, V. H. (2015) · The Neuroscientist · doi:10.1177/1073858414530512 · Cited by 340 · see citing works
Fibrillar Amyloid-β Peptides Activate Microglia via TLR2: Implications for Alzheimer’s Disease
Jana, M., Palencia, C. A., & Pahan, K. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.10.7254 · Cited by 330 · see citing works
Function of microglia and macrophages in secondary damage after spinal cord injury
Ren, Y., Zhou, X., & He, X. (2014) · Neural Regeneration Research · doi:10.4103/1673-5374.143423 · Cited by 317 · see citing works
Self-citation
Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system
Yamada, Y., Doi, T., Hamakubo, T., & Kodama, T. (1998) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050191 · Cited by 267 · see citing works
Aβ-degrading enzymes: potential for treatment of Alzheimer disease
Miners, J. S., Barua, N., Kehoe, P. G., Gill, S., & Love, S. (2011) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182345e46 · Cited by 265 · see citing works
Production and functions of IL-33 in the central nervous system
Yasuoka, S., Kawanokuchi, J., Parajuli, B., Jin, S., Doi, Y., Noda, M., Sonobe, Y., Takeuchi, H., Mizuno, T., & Suzumura, A. (2011) · Brain Research · doi:10.1016/j.brainres.2011.02.045 · Cited by 222 · see citing works
Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease
Fu, A. K. Y., Hung, K.-W., Huang, H., Gu, S., Shen, Y., Cheng, E. Y. L., Ip, F. C. F., Huang, X., Fu, W.-Y., & Ip, N. Y. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1405803111 · Cited by 201 · see citing works
Self-citation
Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease
Chapuis, J., Hot, D., Hansmannel, F., Kerdraon, O., Ferreira, S., Hubans, C., Maurage, C. A., Huot, L., Bensemain, F., Laumet, G., et al. (2009) · Molecular Psychiatry · doi:10.1038/mp.2009.10 · Cited by 201 · see citing works
IL-33 Reduces Macrophage Foam Cell Formation
McLaren, J. E., Michael, D. R., Salter, R. C., Ashlin, T. G., Calder, C. J., Miller, A. M., Liew, F. Y., & Ramji, D. P. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000520 · Cited by 184 · see citing works
Self-citation
Neprilysin-sensitive Synapse-associated Amyloid-β Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function
Huang, S.-M., Mouri, A., Kokubo, H., Nakajima, R., Suemoto, T., Higuchi, M., Staufenbiel, M., Noda, Y., Yamaguchi, H., Nabeshima, T., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601372200 · Cited by 179 · see citing works
Amyloid β-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin
Malito, E., Hulse, R. E., & Tang, W.-J. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8112-4 · Cited by 176 · see citing works
Macrophage scavenger receptors and foam cell formation
de Villiers, W. J. S., & Smart, E. J. (1999) · Journal of Leukocyte Biology · doi:10.1002/jlb.66.5.740 · Cited by 173 · see citing works
Efficient isolation of live microglia with preserved phenotypes from adult mouse brain
Nikodémová, M., & Watters, J. J. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-147 · Cited by 165 · see citing works
A hippocampal Cdk5 pathway regulates extinction of contextual fear
Sananbenesi, F., Fischer, A., Wang, X., Schrick, C., Neve, R. L., Radulović, J., & Tsai, L. (2007) · Nature Neuroscience · doi:10.1038/nn1943 · Cited by 141 · see citing works
Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice
Minogue, A. M., Jones, R. S., Kelly, R. J., McDonald, C., Connor, T. J., & Lynch, M. A. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.12.026 · Cited by 108 · see citing works
Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice
Iwata, N., Sekiguchi, M., Hattori, Y., Takahashi, A., Asai, M., Ji, B., Higuchi, M., Staufenbiel, M., Muramatsu, S., & Saido, T. C. (2013) · Scientific Reports · doi:10.1038/srep01472 · Cited by 107 · see citing works
The Evolving Biology of Microglia in Alzheimer's Disease
Malm, T. M., Jay, T. R., & Landreth, G. E. (2015) · Neurotherapeutics · doi:10.1007/s13311-014-0316-8 · Cited by 74 · see citing works
Immunotherapy for Alzheimer’s disease: past, present and future
Spencer, B. J., & Masliah, E. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00114 · Cited by 73 · see citing works
Parenchymal Microglia of Naıve Adult C57BL/6J Mice Express High Levels of B7.1, B7.2, and MHC Class II
Zhang, G., Li, J., Ventura, E. S., & Rostami, A. M. (2002) · Experimental and Molecular Pathology · doi:10.1006/exmp.2002.2441 · Cited by 64 · see citing works
ST2 Negatively Regulates TLR2 Signaling, but Is Not Required for Bacterial Lipoprotein-Induced Tolerance
Liu, J., Buckley, J. M., Redmond, H. P., & Wang, J. H. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904127 · Cited by 62 · see citing works
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 61 · see citing works
Revisiting the framework of the National Institute on Aging‐Alzheimer's Association diagnostic criteria
Carrillo, M. C., Dean, R. A., Nicolas, F., Miller, D. S., Berman, R., Khachaturian, Z. S., Bain, L. J., Schindler, R. J., & Knopman, D. S. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.05.1762 · Cited by 61 · see citing works
Implication of IL-33 gene polymorphism in Chinese patients with Alzheimer's disease
Yu, J.-T., Song, J.-H., Wang, N.-D., Wu, Z.-C., Zhang, Q., Zhang, N., Zhang, W., Xuan, S.-Y., & Tan, L. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.07.003 · Cited by 54 · see citing works
Research progress on interleukin-33 and its roles in the central nervous system
Han, P., Mi, W., & Wang, Y.-Q. (2011) · Neuroscience Bulletin · doi:10.1007/s12264-011-1025-5 · Cited by 41 · see citing works
α-TLR2 antibody attenuates the Aβ-mediated inflammatory response in microglia through enhanced expression of SIGIRR
Costello, D. A., Carney, D. G., & Lynch, M. A. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.01.005 · Cited by 40 · see citing works
Anemoside A3 Enhances Cognition through the Regulation of Synaptic Function and Neuroprotection
Ip, F. C. F., Fu, W., Cheng, E. Y., Tong, E. P. S., Lok, K.-C., Liang, Y., Ye, W., & Ip, N. Y. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.37 · Cited by 28 · see citing works
Self-citation

Flagged first, then by citations

1 of the 61 references couldn’t be matched to a known paper.

Sorted by citations

Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?
Leng, F., & Edison, P. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-020-00435-y · Cited by 3,179 · see citing works
Interleukin-33 in health and disease
Liew, F. Y., Girard, J., & Turnquist, H. R. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.95 · Cited by 1,157 · see citing works
Self-citation
Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity
Mantovani, A., Dinarello, C. A., Molgora, M., & Garlanda, C. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.012 · Cited by 1,046 · see citing works
Microglia polarization from M1 to M2 in neurodegenerative diseases
Guo, S., Wang, H., & Yin, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.815347 · Cited by 920 · see citing works
Inflammasome signalling in brain function and neurodegenerative disease
Heneka, M. T., McManus, R. M., & Latz, E. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0055-7 · Cited by 836 · see citing works
Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development
Vainchtein, I. D., Chin, G., Cho, F. S., Kelley, K. W., Miller, J. G., Chien, E. C., Liddelow, S. A., Nguyen, P. T., Nakao-Inoue, H., Dorman, L. C., et al. (2018) · Science · doi:10.1126/science.aal3589 · Cited by 657 · see citing works
Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity
Nguyen, P. T., Dorman, L. C., Pan, S., Vainchtein, I. D., Han, R. T., Nakao-Inoue, H., Taloma, S. E., Barron, J. J., Molofsky, A. B., Kheirbek, M. A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.050 · Cited by 615 · see citing works
“Interestingly, clearance of ECM and exogenous recombinant IL-33 are beneficial in mouse models of Alzheimer’s disease (Fu et al., 2016; Végh et al., 2014b).”
Neuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638 · see citing works
“Furthermore, IL-33 injection reduced microglial reactivity, Aβ plaques, synaptic loss and cognitive deficits in a mouse model of AD 488 .”
Microglia regulation of synaptic plasticity and learning and memory
Zhou, M., Cornell, J., Salinas, S., & Huang, H.-Y. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.322423 · Cited by 548 · see citing works
“PTSD mice have decreased mushroom and stubby dendritic spine density in the CA1 region of the hippocampus, which is indicative of synaptic dysregulation that may lead to learning and memory impairments.”
BackgroundInfluential
Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532 · see citing works
Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases
Cardoso, A. L., Fernandes, A. M. A., Aguilar‐Pimentel, J. A., de Angelis, M. H., Guedes, J. R., Brito, M. A., Ortolano, S., Pani, G., Athanasopoulou, S., Gonos, E. S., et al. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.07.004 · Cited by 471 · see citing works
Practical considerations for choosing a mouse model of Alzheimer’s disease
Jankowsky, J. L., & Zheng, H. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0231-7 · Cited by 449 · see citing works
Astrocytes and microglia: In sickness and in health
Vainchtein, I. D., & Molofsky, A. V. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.01.003 · Cited by 450 · see citing works
Brain Pericytes As Mediators of Neuroinflammation
Rustenhoven, J., Jansson, D., Smyth, L. C., & Dragunow, M. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.12.001 · Cited by 371 · see citing works
Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice
Ou, Z., Kong, X., Sun, X., He, X., Zhang, L., Gong, Z., Huang, J., Xu, B., Long, D., Li, J., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.12.009 · Cited by 370 · see citing works
Transcriptional signature in microglia associated with Aβ plaque phagocytosis
Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23111-1 · Cited by 357 · see citing works
Microglia in the Neuroinflammatory Pathogenesis of Alzheimer’s Disease and Related Therapeutic Targets
Cai, Y., Liu, J., Wang, B., Sun, M., & Yang, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.856376 · Cited by 351 · see citing works
Inflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models
Spangenberg, E. E., & Green, K. N. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.07.003 · Cited by 352 · see citing works
Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage
Zhu, H., Wang, Z., Yu, J., Yang, X., He, F., Liu, Z., Che, F., Chen, X., Ren, H., Hong, M., et al. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.03.003 · Cited by 319 · see citing works
The IL-1β phenomena in neuroinflammatory diseases
Mendiola, A. S., & Cardona, A. E. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1732-9 · Cited by 311 · see citing works
Sodium rutin ameliorates Alzheimer’s disease–like pathology by enhancing microglial amyloid-β clearance
Pan, R., Ma, J., Kong, X.-X., Wang, X., Li, S., Qi, X., Yan, Y., Cheng, J., Liu, Q., Jin, W., et al. (2019) · Science Advances · doi:10.1126/sciadv.aau6328 · Cited by 290 · see citing works
Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials
Miao, J., Ma, H., Yang, Y., Liao, Y., Lin, C., Zheng, J., Yu, M., & Lan, J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1201982 · Cited by 293 · see citing works
Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice
Gong, Z., Huang, J., Xu, B., Ou, Z., Zhang, L., Lin, X., Ye, X., Kong, X., Long, D., Sun, X., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1450-3 · Cited by 259 · see citing works
“Activated glia stimulated by Aβ has been reported to upregulate the expression of several proinflammatory chemokines and cytokines including IL-1β, IL-6, and TNF-α, which could result in an increase of Aβ production, neuronal death, and cognitive deficits [19].”
Advances in the development of new biomarkers for Alzheimer’s disease
Klyucherev, T. O., Olszewski, P., Shalimova, A. A., Chubarev, V. N., Tarasov, V. V., Attwood, M. M., Syvänen, S., & Schiöth, H. B. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00296-z · Cited by 241 · see citing works
“IL-33 is commonly associated with inflammation; however, in AD it plays a protective role through stimulation of microglia and subsequent reduction of Aβ plaques in mouse models [118].”
Background
Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia
Uemura, M. T., Maki, T., Ihara, M., Lee, V. M. ‐., & Trojanowski, J. Q. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00080 · Cited by 239 · see citing works
The 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 218 · see citing works
<i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions
Liu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214 · see citing works
“ARG1-positive microglia have been shown to modify Aβ accumulation (79), and IL-33 ameliorated AD-associated phenotypes by promoting anti-inflammatory functions, which included induction of Arg1 (80).”
Background
Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro
Ding, B., Lin, C., Liu, Q., He, Y., Ruganzu, J. B., Jin, H., Peng, X., Ji, S., Ma, Y., & Yang, W. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01981-4 · Cited by 208 · see citing works
“Activated microglia and astrocytes stimulated by Aβ play an important role in the release of pro-inflammatory chemokines and cytokines, which can lead to an increase in Aβ production, neuronal damage, and cognitive deficits [35].”
Background
Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases
Wu, A., Zhou, X., Qiao, G., Yu, L., Tang, Y., Yan, L., Qiu, W., Pan, R., Yu, C., Law, B. Y. K., et al. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101202 · Cited by 193 · see citing works
Self-citation
TREM2 dependent and independent functions of microglia in Alzheimer’s disease
Hou, J., Chen, Y., Grajales-Reyes, G., & Colonna, M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00588-y · Cited by 191 · see citing works
Interactions of glial cells with neuronal synapses, from astrocytes to microglia and oligodendrocyte lineage cells
Liu, Y., Shen, X. P., Zhang, Y., Zheng, X., Cepeda, C., Wang, Y., Duan, S., & Tong, X. (2023) · Glia · doi:10.1002/glia.24343 · Cited by 190 · see citing works
“However, the activation of microglia, either by LPS injections or in other neurodevelopmental and psychiatric disorders, causes exacerbated synaptic activities, leading to deficits in learning and cognition in AD (Fu et al., 2016; Kim et al., 2017; Li et al., 2021; Zuckerman et al., 2018).”
Background
Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease
Dionisio-Santos, D. A., Olschowka, J. A., & O’Banion, M. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1453-0 · Cited by 184 · see citing works
“IL-33 levels are low in the brains of AD patients, and serum levels of soluble ST2, the IL-33 receptor, are high in the brains of patients with mild cognitive impairment [179, 180].”
Background
Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation
Ye, X., Zhu, M., Che, X., Wang, H., Liang, X., Wu, C., Xue, X., & Yang, J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1644-8 · Cited by 184 · see citing works
Targeting neuroinflammation in Alzheimer’s disease: from mechanisms to clinical applications
Si, Z.-Z., Zou, C.-J., Mei, X., Mei, X., Luo, H., Shen, Y., Hu, J., Li, X.-X., Wu, L., & Liu, Y. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.353484 · Cited by 192 · see citing works
“Cytokines and Immune Signaling in Alzheimer’s Disease Over the years, many natural immune cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-10, IL-12, IL-18, IL-23, IL-33, IL-34, IL-1β, and type I interferon, have been suggested to be tightly related to diverse AD processes (Mizuno et al., 2011; Bha…”
Background
IL-4/STAT6 signaling facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice
Xu, J., Chen, Z., Yu, F., Liu, H., Ma, C., Xie, D., Hu, X., Leak, R. K., Chou, S. H. Y., Stetler, R. A., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2018497117 · Cited by 180 · see citing works
“IL-33 also enhances microglial clearance of β-amyloid by activating the ST2/p38 signaling, reducing cerebral inflammation and rescuing memory deficits in Alzheimer’s disease models (38).”
Background
Alarmins: Feel the Stress
Rider, P., Voronov, E., Dinarello, C. A., Apte, R. N., & Cohen, I. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601342 · Cited by 178 · see citing works
“Although the reports of novel alarmins or stressorins and their function in immune activation are rapidly on the rise, uncovering the full potential of their inhibition as a new therapeutic approach will require extensive study of the intracellular pathways leading to their release and inactivation under different phy…”
Background
Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33
Michaudel, C., Mackowiak, C., Maillet, I., Fauconnier, L., Akdiş, C. A., Sokołowska, M., Dreher, A., Tan, H. T., Quesniaux, V. F. J., Ryffel, B., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.11.044 · Cited by 172 · see citing works
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 · see citing works
Circulating levels of IL-1 family cytokines and receptors in Alzheimer’s disease: new markers of disease progression?
Italiani, P., Puxeddu, I., Napoletano, S., Scala, E., Melillo, D., Manocchio, S., Angiolillo, A., Migliorini, P., Boraschi, D., Vitale, E., et al. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1376-1 · Cited by 149 · see citing works
Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus
Wang, Y., Fu, W., Cheung, K., Hung, K.-W., Chen, C., Geng, H.-Y., Yung, W., Qu, J. Y., Fu, A. K. Y., & Ip, N. Y. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2020810118 · Cited by 135 · see citing works
“It has been reported that Alzheimer’s disease patients also exhibited decreased IL-33 transcript levels in the brain and impaired IL-33/ST2 signaling (37, 80).”
BackgroundResultSelf-citation
Targeting Neuroinflammation as a Therapeutic Strategy for Alzheimer’s Disease: Mechanisms, Drug Candidates, and New Opportunities
Fu, W., Wang, X., & Ip, N. Y. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00402 · Cited by 136 · see citing works
Self-citation
The IL-1 family cytokines and receptors in autoimmune diseases
Migliorini, P., Italiani, P., Pratesi, F., Puxeddu, I., & Boraschi, D. (2020) · Autoimmunity Reviews · doi:10.1016/j.autrev.2020.102617 · Cited by 134 · see citing works
The immune system and psychiatric disease: a basic science perspective
Bennett, F. C., & Molofsky, A. V. (2019) · Clinical & Experimental Immunology · doi:10.1111/cei.13334 · Cited by 133 · see citing works
Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer's disease: the emerging role for microglia?
Piirainen, S., Youssef, A. M., Song, C., Kalueff, A. V., Landreth, G. E., Malm, T., & Tian, L. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.046 · Cited by 125 · see citing works
IL-33 exacerbates liver sterile inflammation by amplifying neutrophil extracellular trap formation
Yazdani, H. O., Chen, H., Tohme, S. T., Tai, S., van der Windt, D. J., Loughran, P., Rosborough, B. R., Sud, V., Beer–Stolz, D., Turnquist, H. R., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.09.010 · Cited by 127 · see citing works
Modulating the polarization phenotype of microglia – A valuable strategy for central nervous system diseases
Long, Y., Li, X., Deng, J., Ye, Q., Li, D., Ma, Y., Wu, Y., Hu, Y., He, X.-F., Wen, J., et al. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102160 · Cited by 127 · see citing works
Innate immune alterations are elicited in microglial cells before plaque deposition in the Alzheimer’s disease mouse model 5xFAD
Boza‐Serrano, A., Yang, Y., Paulus, A., & Deierborg, T. (2018) · Scientific Reports · doi:10.1038/s41598-018-19699-y · Cited by 123 · see citing works
“For instance, p38 MAPK protein has been linked with microglial response by directly promoting the expression of inflammatory cytokine such as TNF-α, IL6 or IL-1β via TLR’s ligands or in the presence of Aβ37.”
IL-1 family cytokines in inflammation and immunity
Garlanda, C., Ceglie, I. D., & Jaillon, S. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01358-8 · Cited by 143 · see citing works
“In AD animal models, IL-33 expression has been associated with reduced disease pathology, whereas increased IL-33 plasma levels have been observed in patients treated with the neuroprotective compound homotaurine [247, 248].”
IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice.
He, R., Yin, H., Yuan, B., Liu, T., Luo, L., Huang, P., Dai, L., & Zeng, K. (2017) · Molecular Immunology · doi:10.1016/j.molimm.2017.06.249 · Cited by 111 · see citing works
“…variety of studies that IL-33, known as an inducer of Th2type immune response, exhibits a central role in the treatment of situations such as stroke, transplantation, experimental autoimmune uveitis and Alzheimer's disease (Luo et al., 2015; Yin et al., 2010; Barbour et al., 2014; Fu et al., 2016).”
Background
Synaptic Elimination in Neurological Disorders
Cardozo, P. L., de Lima, I. B. Q., Maciel, E. M. A., Silva, N. C., Dobránsky, T., & Ribeiro, F. M. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666190603170511 · Cited by 113 · see citing works
The role of innate immunity in Alzheimer's disease
Ennerfelt, H. E., & Lukens, J. R. (2020) · Immunological Reviews · doi:10.1111/imr.12896 · Cited by 121 · see citing works
Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility
Russi, A. E., Ebel, M. E., Yang, Y., & Brown, M. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710401115 · Cited by 117 · see citing works
IL-33-PU.1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in Alzheimer’s Disease
Lau, S.-F., Chen, C., Fu, W.-Y., Qu, J. Y., Cheung, T. H., Fu, A. K. Y., & Ip, N. Y. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107530 · Cited by 114 · see citing works
“IL-33 Enhances the Chemotactic Response of a Microglial Subpopulation toward AbPlaques in APP/PS1 Mice IL-33 injection enhances the co-localization of microglia with Ab plaques and promotes Ab clearance (Fu et al., 2016).”
BackgroundInfluentialSelf-citation
Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease
Uddin, M. S., Kabir, M. T., Mamun, A. A., Barreto, G. E., Rashid, M., Perveen, A., & Ashraf, G. M. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106479 · Cited by 115 · see citing works
TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway
Ruganzu, J. B., Zheng, Q., Wu, X., He, Y., Peng, X., Jin, H., Zhou, J., Ma, R., Ji, S., Ma, Y., et al. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113506 · Cited by 115 · see citing works
Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer's Disease Pathogenesis
Kempuraj, D., Selvakumar, G. P., Thangavel, R., Ahmed, M. E., Zaheer, S. A., Raikwar, S. P., Iyer, S. S., Bhagavan, S., Ramaswamy, S. B., & Zaheer, A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00703 · Cited by 104 · see citing works
“However, another study showed that injection of IL33 led to improved memory deficit in APP/PS1 AD mice model (Fu et al., 2016).”
Background
The dual face of microglia (M1/M2) as a potential target in the protective effect of nutraceuticals against neurodegenerative diseases
Darwish, S. F., Elbadry, A. M. M., Elbokhomy, A. S., Salama, G. A., & Salama, R. M. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1231706 · Cited by 106 · see citing works
“Alzheimer’s disease is the prevailing type of dementia, associated with damaged locomotor ability, thinking, judgment ability, increasing memory loss, and cognitive decline (Fu et al., 2016).”
Background
Expression and Function of IL-33/ST2 Axis in the Central Nervous System Under Normal and Diseased Conditions
Fairlie‐Clarke, K. J., Barbour, M., Wilson, C., Hridi, S. U., Allan, D., & Jiang, H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02596 · Cited by 100 · see citing works
“Patients with mild cognitive impairment, who have an increased risk of AD development, also exhibit a significantly higher serum level of sST2 (52).”
Background
Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease
Kong, F., Jiang, X., Wang, R., Zhai, S., Zhang, Y., & Wang, D. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01967-2 · Cited by 99 · see citing works
“Aβ can activate neuroglia and stimulate the expression of pro-inflammatory chemokines such as TNF-α and ILs, perhaps leading to increased Aβ production and neuronal death [36, 37].”
Background
Autoimmune Neuroinflammatory Diseases: Role of Interleukins
Khan, A. W., Farooq, M., Hwang, M.-J., Haseeb, M., & Choi, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24097960 · Cited by 104 · see citing works
Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review)
Qin, P., Sun, Y., & Li, L. (2024) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2024.5371 · Cited by 104 · see citing works
“Excessive activation of microglial cells and reduced phagocytic ability leads to increased accumula‑ tion of A β plaques and τ hyperphosphorylation, exacerbating neuroinflammation (164).”
Background
Artemisinin Improved Neuronal Functions in Alzheimer's Disease Animal Model 3xtg Mice and Neuronal Cells via Stimulating the ERK/CREB Signaling Pathway
Zhao, X., Li, S., Gaur, U., & Zheng, W. (2020) · Aging and Disease · doi:10.14336/ad.2019.0813 · Cited by 91 · see citing works
“AD is one of the neurodegenerative disorders that affects older population and is clinically characterized by progressive loss of memory along with decline in multiple cognitive abilities [42, 43].”
Background
Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits
Scholtzova, H., Do, E., Dhakal, S., Sun, Y., Liu, S., Mehta, P. D., & Wisniewski, T. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.1967-16.2016 · Cited by 82 · see citing works
“Similarly, APP/PS1 mice treatment with IL33, which skews microglia toward an alternative activation state with enhanced phagocytic capacity, resulted in AD pathology amelioration in association with Iba1 microglia in the vicinity of amyloid deposits (Fu et al., 2016).”
Background
Deletion of the Inflammasome Sensor Aim2 Mitigates Aβ Deposition and Microglial Activation but Increases Inflammatory Cytokine Expression in an Alzheimer Disease Mouse Model
Wu, P.-J., Hung, Y.-F., Liu, H., & Hsueh, Y. (2017) · NeuroImmunoModulation · doi:10.1159/000477092 · Cited by 84 · see citing works
IL-33/ST2 plays a critical role in endothelial cell activation and microglia-mediated neuroinflammation modulation
Cao, K., Liao, X., Lü, J., Yao, S., Wu, F., Zhu, X., Shi, D., Wen, S., Liu, L., & Zhou, H. Y. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1169-6 · Cited by 84 · see citing works
“have shown that IL-33 ameliorated cognitive decline in an animal model of Alzheimer’s disease [38].”
The Cyanthin Diterpenoid and Sesterterpene Constituents of Hericium erinaceus Mycelium Ameliorate Alzheimer’s Disease-Related Pathologies in APP/PS1 Transgenic Mice
Tzeng, T.-T., Chen, C.-C., Chen, C.-C., Tsay, H., Lee, L.-Y., Chen, W.-P., Shen, C.-C., & Shiao, Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020598 · Cited by 81 · see citing works
Early Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review
Lemche, E. (2018) · Current Genomics · doi:10.2174/1389202919666171229145156 · Cited by 82 · see citing works
Clinical pet imaging of microglial activation: Implications for microglial therapeutics in alzheimer’s disease
Shen, Z., Bao, X., & Wang, R. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00314 · Cited by 77 · see citing works
Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia
Benítez, D. P., Jiang, S., Wood, J. I., Wang, R., Hall, C. M., Peerboom, C., Wong, N. S. M., Stringer, K. M., Vitanova, K. S., Smith, V. C., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00457-0 · Cited by 79 · see citing works
“Extending that role into a transgenic mouse model of Alzheimer’s disease, IL33 shifted the activation state of microglia from a proinflammatory profile towards a profile expressing anti-inflammatory genes with improved phagocytosis and again improved fearconditioned learning [64].”
Background
An “Amyloid‐β Cleaner” for the Treatment of Alzheimer's Disease by Normalizing Microglial Dysfunction
Liu, R., Yang, J., Liu, L., Lü, Z., Shi, Z., Ji, W., Shen, J., & Zhang, X. (2019) · Advanced Science · doi:10.1002/advs.201901555 · Cited by 79 · see citing works
Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease
Yang, Y., & Zhang, Z. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00110 · Cited by 76 · see citing works
Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice
He, Z., Yang, Y., Xing, Z., Zuo, Z., Wang, R., Gu, H., Qi, F., & Yao, Z. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2644-4 · Cited by 77 · see citing works
IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia
Rivera-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 · see citing works
IL-33 and its decoy sST2 in patients with Alzheimer’s disease and mild cognitive impairment
Saresella, M., Marventano, I., Piancone, F., La Rosa, F., Galimberti, D., Fenoglio, C., Scarpini, E., & Clerici, M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01806-4 · Cited by 75 · see citing works
Lychee seed polyphenol protects the blood–brain barrier through inhibiting Aβ(25–35)‐induced NLRP3 inflammasome activation via the AMPK / mTOR / ULK1‐mediated autophagy in bEnd .3 cells and APP / PS1 mice
Xiong, R., Zhou, X., Tang, Y., Wu, J., Sun, Y., Teng, J., Pan, R., Law, B. Y. K., Zhao, Y., Qiu, W., et al. (2020) · Phytotherapy Research · doi:10.1002/ptr.6849 · Cited by 78 · see citing works
“The expression of ZO-1 and Claudin 5 in endothelial cells of tissue was detected by immunohistochemical method as previously described (Fu et al., 2016).”
MethodSelf-citation
Macrophages originated IL-33/ST2 inhibits ferroptosis in endometriosis via the ATF3/SLC7A11 axis
Wu, Q., Liang, Z., Jiang, J., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06182-4 · Cited by 74 · see citing works
“It is also worth mentioning that IL-33 induces macrophage anti-in ﬂ ammatory polarization and stimulates the formation of splenic red pulp macrophages (RPMs) that regulate erythrocyte homeostasis and support iron recycling [9, 10].”
Neuroinflammatory challenges compromise neuronal function in the aging brain: Postoperative cognitive delirium and Alzheimer’s disease
Cortese, G. P., & Bürger, C. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.08.027 · Cited by 74 · see citing works
The neuroinflammatory role of microglia in Alzheimer's disease and their associated therapeutic targets
AmeliMojarad, M., & AmeliMojarad, M. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14856 · Cited by 73 · see citing works
Instructive roles of astrocytes in hippocampal synaptic plasticity: neuronal activity‐dependent regulatory mechanisms
Wang, Y., Fu, A. K. Y., & Ip, N. Y. (2021) · FEBS Journal · doi:10.1111/febs.15878 · Cited by 71 · see citing works
Self-citation
Ginsenoside RK1 improves cognitive impairments and pathological changes in Alzheimer's disease via stimulation of the AMPK/Nrf2 signaling pathway
She, L., Sun, J., Li, X., Li, A., Li, L., Wu, H., Ren, J., Wang, W., Liang, G., & Zhao, X. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.155168 · Cited by 81 · see citing works
Roles of Cytokines in Alzheimer’s Disease
Chen, Z., Balachandran, Y. L., Chong, W. P., & Chan, K. W. Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115803 · Cited by 71 · see citing works
“Microglia are professional phagocytes and play a critical role in A β plaque clearance in the AD brain [3].”
BackgroundInfluential
Neurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders
Kempuraj, D., Dourvetakis, K. D., Cohen, J., Valladares, D. S., Joshi, R. S., Kothuru, S. P., Anderson, T., Chinnappan, B., Cheema, A. K., Klimas, N. G., et al. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1491952 · Cited by 75 · see citing works
Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions
Noh, M., Kwon, H. S., Kwon, M., Nahm, M., Jin, H. K., Bae, J., & Kim, S. H. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00867-4 · Cited by 85 · see citing works
“Interleukin (IL) − 33, a cytokine belonging to the IL-1 family, also promotes microglial recruitment and Aβ clearance through the ST2/p38 signaling pathway, leading to a reduction in soluble Aβ and amyloid plaque burden [124].”
The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
Lau, S.-F., Wu, W., Wong, H. Y., Ouyang, L., Qiao, Y., Xu, J., Lau, J. H.-Y., Wong, C., Jiang, Y., Holtzman, D. M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00491-1 · Cited by 70 · see citing works
Self-citation
The Role of Vascular Cells in Pancreatic Beta-Cell Function
Burganova, G., Bridges, C. A., Thorn, P., & Landsman, L. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.667170 · Cited by 65 · see citing works
IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke
Zhang, S. R., Piepke, M., Chu, H. X., Broughton, B. R. S., Shim, R., Wong, C. H. Y., Lee, S., Evans, M. A., Vinh, A., Sakkal, S., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.121560 · Cited by 67 · see citing works
IL33 (Interleukin 33)/ST2 (Interleukin 1 Receptor-Like 1) Axis Drives Protective Microglial Responses and Promotes White Matter Integrity After Stroke
Xie, D., Liu, H., Xu, F., Su, W., Ye, Q., Yu, F., Austin, T. J., Chen, J., & Hu, X. (2021) · Stroke · doi:10.1161/strokeaha.120.032444 · Cited by 66 · see citing works
Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer’s disease alleviates amyloid-related pathologies in mice
Duan, Y., Tao, Y., Qu, Z., Chen, Y., Miranda, A., Zhou, X., Lok, K.-C., Chen, Y., Fu, A. K. Y., Gradinaru, V., et al. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00759-0 · Cited by 64 · see citing works
Self-citation
Type 2 immunity in the brain and brain borders
Mamuladze, T., & Kipnis, J. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-01043-8 · Cited by 65 · see citing works
In Vivo Near-Infrared Two-Photon Imaging of Amyloid Plaques in Deep Brain of Alzheimer’s Disease Mouse Model
Chen, C., Liang, Z., Zhou, B., Li, X., Lui, C., Ip, N. Y., & Qu, J. Y. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00306 · Cited by 63 · see citing works
Self-citation
Dual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation
Rao, X., Hua, F., Zhang, L., Lin, Y., Fang, P., Chen, S., Ying, J., & Wang, X. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03570-w · Cited by 64 · see citing works
“IL-33 treatment significantly reversed the LTP impairment and contextual memory deficits of APP/PS1 mice, while also improving habituation to a new environment, which confirmed that IL-33 treatment reversed the reduction of synaptic plasticity in the hippocampus and cognitive deficits in APP/PS1 mice [2, 24].”
BackgroundInfluential
Interleukin‐33 regulates tissue remodelling and inhibits angiogenesis in the eye
Theodoropoulou, S., Copland, D. A., Liu, J., Wu, J., Gardner, P. J., Ozaki, E., Doyle, S., Campbell, M. D., & Dick, A. D. (2016) · The Journal of Pathology · doi:10.1002/path.4816 · Cited by 62 · see citing works
“IL-33 prevents cognitive decline in mouse models of Alzheimer’s disease [47] and inhibits atherosclerosis [45], and here IL-33 also directly inhibited choroidal fibroblast activity, implicating a potentially wider role clinically.”
Background
Impact of aging immune system on neurodegeneration and potential immunotherapies
Liang, Z., Zhao, Y., Ruan, L., Zhu, L., Jin, K., Zhuge, Q., Su, D., & Zhao, Y. L. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.07.006 · Cited by 61 · see citing works
“However, it was recently reported that serum levels of soluble ST2, a decoy receptor for IL-33, significantly increased in patients with mild cognitive impairment, indicating that impaired IL-33/ST2 signaling pathwaymaycontribute to the pathogenesis of AD in APP/PS1mice (Fu et al., 2016).”
Targeting IL-33/ST2 signaling: regulation of immune function and analgesia
Fattori, V., Hohmann, M., Rossaneis, A. C., Manchope, M. F., Alves-Filho, J., Cunha, T., Cunha, F., & Verri, W. (2017) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2017.1398734 · Cited by 61 · see citing works
“In fact, immunohistochemical analysis of spinal cord tissue after SCI demonstrated that rIL-33 treatment decreases the activation of astrocytes but does not alter microglial activity in vivo [33], despite evidence indicating that microglia express ST2 given IL-33 induce M2 polarization or activation of microglia in vi…”
Targeting the IL33–NLRP3 axis improves therapy for experimental cerebral malaria
Strangward, P., Haley, M., Albornoz, M. G., Barrington, J., Shaw, T. N., Dookie, R. S., Zeef, L. A. H., Baker, S. M., Winter, E., Tzeng, T.-C. J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1801737115 · Cited by 60 · see citing works
“(A) Peripheral parasitemia, (B) survival curves, and (C) RMCBS scores of mice after infection (d0) and drug treatment (gray box).”
BackgroundMethodResultInfluentialSelf-citation
The gut microbiome regulates astrocyte reaction to Aβ amyloidosis through microglial dependent and independent mechanisms
Chandra, S., Di Meco, A., Dodiya, H. B., Popovic, J., Cuddy, L. K., Weigle, I. Q., Zhang, X., Sadleir, K., Sisodia, S. S., & Vassar, R. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00635-2 · Cited by 58 · see citing works
Mechanisms of microglia-mediated synapse turnover and synaptogenesis
Ball, J. B., Green‐Fulgham, S. M., & Watkins, L. R. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102336 · Cited by 63 · see citing works
Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice
Carlock, C., Wu, J., Shim, J., Moreno‐González, I., Pitcher, M. R., Hicks, J., Suzuki, A., Iwata, J., Quevado, J., & Lou, Y. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.142 · Cited by 59 · see citing works
The Role of Glial Cells in Synaptic Dysfunction: Insights into Alzheimer's Disease Mechanisms
Yu, Y., Chen, R., Mao, K., Deng, M., & Li, Z. (2023) · Aging and Disease · doi:10.14336/ad.2023.0718 · Cited by 60 · see citing works
“IL-33 also triggered a transition in microglia status and increased phagocytosis of Aβ plaques in APP/PS1 mice [91, 92].”
Background
Inflammasomes and Cell Death: Common Pathways in Microparticle Diseases
Rashidi, M., Wicks, I. P., & Vince, J. E. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.06.005 · Cited by 56 · see citing works

"Lipopolysaccharide-induced animal models for neuroinflammation – An overview."
Silva, A., Fiadeiro, M. B., Bernardino, L. I., Fonseca, C. P., Baltazar, G., & Cristóvão, A. C. (2023) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2023.578273 · Cited by 76 · see citing works
Role of Neuroinflammation in the Trajectory of Alzheimer’s Disease and in vivo Quantification Using PET
Edison, P., & Brooks, D. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179929 · Cited by 41 · see citing works
Characterisation of ReNcells CX and VM stimulated with interleukin-1β and lipopolysaccharide
Cheung, K. A. K., Abeysinghe, P., Vaswani, K., et al. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105326 · Cited by 4 · see citing works
Alzheimer’s Disease Research Using Human Microglia
Lue, L., Beach, T. G., & Walker, D. G. (2019) · Cells · doi:10.3390/cells8080838 · Cited by 26 · see citing works
Differential Regional Vulnerability of the Brain to Mild Neuroinflammation Induced by Systemic LPS Treatment in Mice
Jung, H., Lee, H., Kim, D., Cheong, E., Hyun, Y., Yu, J., & Um, J. W. (2022) · Journal of Inflammation Research · doi:10.2147/jir.s362006 · Cited by 31 · see citing works

Authors: Fu, A. K. Y., Hung, K.-W., Yuen, M. Y. F., Zhou, X., Mak, D. S. Y., Chan, I. C. W., Cheung, T. H., Zhang, B., Fu, W.-Y., Liew, F. Y., & Ip, N. Y.
Affiliations: Hong Kong University of Science and Technology (HK)
Second Affiliated Hospital of Zhejiang University (CN)
Soochow University (CN)
ORCID: Fu, Amy K. Y.
Yuen, Michael Y. F.
Zhou, Xiaopu
Mak, Deejay S. Y.
Chan, Ivy C. W.
Cheung, Tom H.
Zhang, Baorong
Ip, Nancy Y.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2016-04-18
Volume: 113
Issue: 19
Pages: E2705-13
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1604032113
PMC: PMC4868478
OpenAlex: W2342031861
Semantic Scholar: 1eac3f908af98105c0179fde2edb52b24e9f5d0c
Cited by: 369
References: 61
Citations by year: 2026: 18 · 2025: 41 · 2024: 45 · 2023: 39 · 2022: 33 · 2021: 48 · 2020: 40 · 2019: 24 · 2018: 35 · 2017: 31 · 2016: 14 · 2012: 1
FWCI: 27.92
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
Keywords: IL-33, Alzheimer's disease, soluble ST2, amyloid-beta, microglial activation, innate immunity, synaptic plasticity, memory impairment, APP/PS1 mice, amyloid plaques, p38 MAPK signaling, microglial polarization, neuroinflammation, NLRP3 inflammasome, IL-1β, interleukin-6
MeSH terms: Interleukin-33, Alzheimer Disease, Animals, Brain, Cognition Disorders, Female, Male, Mice, Transgenic, Cytokines, Treatment Outcome, Neuroprotective Agents, Mice

About these checks

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline

Abstract

AI snapshot

TL;DR

Key findings

Methods

Limitations

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks