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IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
Open accessAbstract
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.
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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.
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In the paper
“IL-33 injection further increased the proportion of CD11b + cells exhibiting methoxy-X04 fluorescence (∼47%; Fig. 3 F and G).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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.”
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In the paper
“IL-33 administration increased CD68 expression in Iba1 + myeloid cells, that were in close contact with amyloid plaques (Fig. 3E).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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);”
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In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
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In the paper
“IL-33 injection enhanced the recruitment of Iba1 + myeloid cells to amyloid plaques in these cortices (Fig. 3A).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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.”
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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“IL-33 administration for 2 d also reduced 4G8-stained amyloid plaques in 5XFAD mice, another AD transgenic mouse model (SI Appendix, Fig. S6).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaincorrelationaln = 33- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“(C) ST2-deficient microglia abolished the IL-33stimulated Aβ uptake.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
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In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
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In the paper
“(D and E) IL-33 increases CD68 expression in Aβ plaques.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
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In the paper
“(A and B) IL-33 administration increases neprilysin protein level in the brains of APP/PS1 mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“(A-C) IL-33 increases the colocalization of Iba1 + myeloid cells and Aβ plaques in the cortices of APP/PS1 mice (12 mo old).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 16- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 4- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“IL-33 administration significantly suppressed the increased expression of these proinflammatory genes (Fig. 4 F-H).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
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In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(D) IL-33-treated APP/PS1 mice (14 mo old) exhibit improved habituation in the exploratory open field (OF) test.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 13- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 rescues LTP impairment in APP/PS1 mutant mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The mechanisms underlying the onset and progression of AD remain unclear.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings suggest that IL-33 administration increases phagocytic Aβ uptake by myeloid cells.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these findings suggest that IL-33 regulates inflammatory responses in the APP/PS1 mouse brain.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Discussion · hedged
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings suggest that IL-33-dependent activation of ST2 signaling in microglia enhances Aβ phagocytosis and clearance.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(D and E) IL-33 drives microglia to an alternative activation state in APP/PS1 mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results indicate that ST2 signaling in microglia mediates the IL-33-associated enhancement of Aβ phagocytosis in the brain of APP/PS1 mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 6- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Statistical Analysis. · plain
In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
What the sources say
- Not checked yetcites [15] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 modulates inflammatory responses in APP/PS1 mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 specifically enhances Aβ uptake by microglia.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- The quote only partly states this claim. 3
- It may state two separate claims as one. 6
- Probably not a substantial claim. 2
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 rescues LTP impairment in APP/PS1 mutant mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 ameliorates memory retrieval deficits of APP/PS1 mice in fear conditioning (FC) tests.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 ameliorates memory retrieval deficits of APP/PS1 mice in fear conditioning (FC) tests.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 administration ameliorates synaptic impairment and behavioral deficits in APP/PS1 mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that IL-33 treatment reverses contextual memory deficits in APP/PS1 mice, probably through ameliorating the hippocampal synaptic dysfunctions.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Results
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-33 administration reduces soluble Aβ levels and Aβ plaques in APP/PS1 mice.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Statistical Analysis.
plaindirectn = 6- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The purity of microglia/infiltrating monocyte isolation was routinely >90% as determined by fluorescence staining for CD11b and flow cytometry analysis.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Contextual Fear Conditioning.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“IL-33 ameliorated AD-associated phenotypes by promoting anti-inflammatory functions, which included induction of Arg1 (80).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [80]
Citations
Cites
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
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
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
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 3,773
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×
“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).”
BackgroundNLRP3 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
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
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
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
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
Cited by
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
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 1,178
Self-citationInterleukin-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
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
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
Metadata
- 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
- 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
- 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
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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 ›
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