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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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46 Own result · 21 Own interpretation · 3 Not checked yet · 2 Own method
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 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
plaindirect- Asserted: passes — The authors put it forward as true.
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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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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“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
plaindirectn = 3- Asserted: passes — The authors put it forward as true.
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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.”
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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);”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Results · plain
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
“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.
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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).”
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Results · boosted
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 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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“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.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Results · plain
- 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.
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The quote only partly states this claim.
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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.
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The quote only partly states this claim.
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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.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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.
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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.
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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.
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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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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.
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- 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.
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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.
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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.
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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]
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Items 101–200 of 370
IL-33/ST2 axis in diverse diseases: regulatory mechanisms and therapeutic potential
Sheng, F., Mi, L., Yu, J.-M., Yang, S., Zou, L., Yang, G., & Zhang, L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1533335 · Cited by 71
“Several ideas reveal the potential of the IL-33/ST2 pathway for detecting new biomarkers and therapeutic targets in various brain diseases (53).”
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Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury
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“Moreover, several studies also reported the involvement of 33/ST2 signaling in the pathogenesis of neurological diseases including Alzheimer’s disease [12], experimental autoimmune encephalomyelitis (EAE) [13], experimental cerebral malaria [14], and stroke [15].”
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Therapeutic Opportunities of Interleukin-33 in the Central Nervous System
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“In the APPswe, PSEN1dE9 (APP/PS1) double transgenic mouse, an AD mouse model, IL-33 administration reduces soluble Ab levels and amyloid plaque deposition by enhancing microglial recruitment, Ab phagocytic activity and anti-inflammatory responses via ST2/ MAPK signaling, ultimately contributing to the amelioration of…”
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“Furthermore, the innate immune response may be modulated via polarizing microglia/macrophages in APP/PS1 mice [61].”
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“, IL-1β, IL-6, and NLRP3 inflammasome) [15].”
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Self-citationInterleukin (IL)‐33: an orchestrator of immunity from host defence to tissue homeostasis
Zhou, Z., Yan, F., & Liu, O. (2020) · Clinical & Translational Immunology · doi:10.1002/cti2.1146 · Cited by 53
“Brain-derived IL-33 recruits monocytes and acts on monocytes to augment the differentiation of AAM.(39) This recruitment, together with a decrease in proinflammatory genes, including IL-6, IL-1b and NLRP3, contributes to neuroprotective effects.”
BackgroundInfluentialHippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments
Reverchon, F., de Concini, V., Larrigaldie, V., Benmerzoug, S., Briault, S., Togbe, D., Ryffel, B., Quesniaux, V. F. J., & Menuet, A. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01939-6 · Cited by 50
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Soluble ST2 in Heart Failure: A Clinical Role beyond B-Type Natriuretic Peptide
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“…with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of Alzheimer(cid:31)s disease [24] and an elevation in sST2 serum concentration represents and tracks disease progression. neurological point of view, sST2 levels increase in…”
BackgroundThe role of genetic risk factors of Alzheimer’s disease in synaptic dysfunction
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Guo, H., Bossila, E. A., Ma, X., Zhao, C., & Zhao, Y. X. (2022) · Cells · doi:10.3390/cells11203237 · Cited by 54
Non-Coding RNA in Microglia Activation and Neuroinflammation in Alzheimer’s Disease
He, C., Li, Z., Yang, M., Yu, W., Luo, R., Zhou, J., He, J., Chen, Q., Song, Z., & Cheng, S. (2023) · Journal of Inflammation Research · doi:10.2147/jir.s422114 · Cited by 49
“50 Transforming the phenotype of microglia from an inflammatory state to an anti-inflammatory state in AD mice has been shown to mitigate the detrimental effects caused by Aβ aggregation and facilitate its clearance.”
BackgroundStill, K. M., Batista, S. J., O’Brien, C. A., Oyesola, O. O., Früh, S. P., Webb, L. M., Smirnov, I., Kovacs, M. A., Cowan, M. N., Hayes, N. W., et al. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1009027 · Cited by 49
“A role for IL-33 in stroke [36,37], neurodegeneration [38,39], EAE [40,41], and CNS infection [42–44] has been described, but mechanistic understanding of IL-33 signaling during brain disease is limited.”
BackgroundEngulfed by Glia: Glial Pruning in Development, Function, and Injury across Species
Raiders, S. A., Han, R. T., Scott‐Hewitt, N., Kucenas, S., Lew, D., Logan, M. A., & Singhvi, A. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.1660-20.2020 · Cited by 42
“, 2020), and it also plays important protective roles in the context of neurodegeneration and after injury (Gadani et al., 2015; Pomeshchik et al., 2015; Fu et al., 2016; Lau et al., 2020).”
BackgroundSignaling and functions of interleukin-33 in immune regulation and diseases
Yi, X.-M., Lian, H., & Li, S. (2022) · Cell Insight · doi:10.1016/j.cellin.2022.100042 · Cited by 46
“1) (Gachter et al., 1996).”
Jha, S. K., Jha, N. K., Kumar, D., Sharma, R., Shrivastava, A., Ambasta, R. K., & Kumar, P. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160623 · Cited by 48
IL-33-ST2 Axis in Liver Disease: Progression and Challenge
Sun, Z., Chang, B., Gao, M., Zhang, J., & Zou, Z. (2017) · Mediators of Inflammation · doi:10.1155/2017/5314213 · Cited by 47
“Recently, it has been reported that IL33 can ameliorate AD-like pathology and cognitive decline, and the authors proposed that IL-33 is a promising potential treatment for AD [29].”
BackgroundIL-33/ST2 Pathway as a Rational Therapeutic Target for CNS Diseases
Du, L., Wang, Y., Hua, G., & Mi, W. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.11.028 · Cited by 46
He, Y., Ruganzu, J. B., Zheng, Q., Wu, X., Jin, H., Peng, X., Ding, B., Lin, C., Ji, S., Ma, Y., et al. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01982-7 · Cited by 47
The Role of Interleukin-33 in Patients with Mild Cognitive Impairment and Alzheimer's Disease
Liang, C., Su, K., Tsai, C., Lee, J., Chu, C., Yeh, T., Su, M., Lin, G., Lin, Y., Chu, H., et al. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00652-z · Cited by 48
Zhuang, X., Zhan, B., Jia, Y., Li, C., Wu, N., Zhao, M., Chen, N., Guo, Y., Du, Y., Zhang, Y., et al. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.02.019 · Cited by 48
Life and death of microglia: Mechanisms governing microglial states and fates
Matsudaira, T., & Prinz, M. (2022) · Immunology Letters · doi:10.1016/j.imlet.2022.04.001 · Cited by 47
Liu, M., Huang, J., Liu, T., Yuan, J., Lv, C., Sha, Z., Wu, C., Jiang, W., Liu, X., Nie, M., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01555-4 · Cited by 48
“IL-33 can be released by necrotic cells following tissue damage as an endogenous danger signal or “alarmin” [45], binding to the ST2 protein (the only well-documented receptor for IL-33) to play a complex immunomodulatory role in rodent models of neurological diseases, such as AD, MS, and stroke [18, 38, 40].”
BackgroundInfluentialAlzheimer’s disease pathogenesis: standing at the crossroad of lipid metabolism and immune response
Wang, Z., Zhang, L., & Qin, C. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00857-6 · Cited by 60
Behavioral Changes in Mice Lacking Interleukin-33
Dohi, E., Choi, E. Y., Rose, I. V. L., Murata, A. S., Chow, S., Niwa, M., & Kano, S. (2017) · eNeuro · doi:10.1523/eneuro.0147-17.2017 · Cited by 47
“Furthermore, rodent studies showed that IL-33 had a therapeutic effect in a mouse model of Alzheimer disease, attenuating cellular pathologies and recovering behavioral phenotypes (Fu et al., 2016).”
BackgroundXu, H., Li, D., Ma, J., Zhao, Y., Xu, L., Tian, R., Liu, Y., Sun, L., & Su, J. (2021) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2020.0211 · Cited by 50
Alarmins (IL-33, sST2, HMGB1, and S100B) as potential biomarkers for schizophrenia
Kozłowska, E., Brzezińska‐Błaszczyk, E., Agier, J., Wysokiński, A., & Żelechowska, P. (2021) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2021.04.019 · Cited by 44
Deng, P., Fan, T., Gao, P., Peng, Y., Li, M., Li, J., Qin, M., Hao, R., Wang, L., Li, M., et al. (2024) · Advanced Science · doi:10.1002/advs.202402030 · Cited by 52
Borovčanin, M., Janicijevic, S. M., Jovanović, I., Gajović, N., Arsenijević, N., & Lukić, M. L. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00271 · Cited by 45
“Also, it is reported that IL-33 can modulate microglia in an animal model of Alzheimer‘s disease (55), but its function in these condition is still unclear.”
BackgroundGhosh, P., Singh, R. B., Ganeshpurkar, A., Pokle, A. V., Singh, R. B., Singh, S. K., & Kumar, A. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105212 · Cited by 44
Critical Roles of IL-33/ST2 Pathway in Neurological Disorders
Isnadi, M. F. A. R., Chin, V. K., Majid, R. A., Lee, T. Y., Abdullah, M. A., Bello, R. O., Ibraheem, Z. O., & Basir, R. (2018) · Mediators of Inflammation · doi:10.1155/2018/5346413 · Cited by 42
“Intriguingly, the administration and modulation of IL-33 were found to alleviate the neuropathology of AD in mice by reducing the soluble βA levels and plaque accumulation through the recruitment of βA phagocytic activity and the proinflammatory responses involving of IL-1β, IL6, and NLR family pyrin domain containing…”
Luo, R., Fan, Y., Yang, J., Ye, M., Zhang, D., Guo, K., Li, X., Bi, R., Xu, M., Yang, L.-X., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00748-4 · Cited by 41
Neuroplastic Effect of Exercise Through Astrocytes Activation and Cellular Crosstalk
Li, F., Geng, X., Yun, H. J., Haddad, Y. W., Chen, Y., & Ding, Y. (2021) · Aging and Disease · doi:10.14336/ad.2021.0325 · Cited by 46
Insulin Resistance as a Common Link Between Current Alzheimer’s Disease Hypotheses
Alves, S. S., da Silva-Júnior, R. M. P., Servilha‐Menezes, G., Homolak, J., Šalković‐Petrišić, M., & Garcia‐Cairasco, N. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210234 · Cited by 39
Nosi, D., Lana, D., Giovannini, M. G., Delfino, G., & Zecchi‐Orlandini, S. (2021) · Cells · doi:10.3390/cells10051195 · Cited by 41
New Possibilities in the Therapeutic Approach to Alzheimer’s Disease
Doroszkiewicz, J., & Mroczko, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168902 · Cited by 46
Xing, Z.-H., He, Z.-M., Wang, S., Yan, Y., Zhu, H.-Y., Gao, Y.-G., Zhao, Y., & Zhang, L.-X. (2018) · RSC Advances · doi:10.1039/c8ra05356a · Cited by 35
Huang, D., Liu, M., & Jiang, Y. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28783 · Cited by 37
“ATP production was measured by a luciferase‐based ATP assay kit, purchased from Beyotime, China (Fukumoto et al., 2018).”
MethodInfluentialRole of alarmins in poststroke inflammation and neuronal repair
Sakai, S., & Shichita, T. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00961-5 · Cited by 39
Zhao, K., Liu, J., Sun, T., Zeng, L., Li, Z., Li, Z., & Liu, R. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.02.016 · Cited by 42
Maddur, M. S., Victor, E. S., Das, M., Prakhar, P., Sharma, V. K., Singh, V., Rabin, M., Trinath, J., Balaji, K. N., Bolgert, F., et al. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0818-5 · Cited by 35
“Conclusions Because of its role as promoter of type 2 immune responses and regulator of innate and adaptive immune responses, IL-33 has been explored as therapeutic option in pre-clinical models of Alzheimer’s disease [37], stroke [38], cerebral malaria [39], and transplantation [40].”
Han, Z., Xue, W., Tao, L., & Zhu, F. (2018) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13051 · Cited by 36
Astrocyte subtype-specific approach to Alzheimer's disease treatment
Sarkar, S., & Biswas, S. C. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104956 · Cited by 35
Biological Role, Mechanism of Action and the Importance of Interleukins in Kidney Diseases
Mertowska, P., Mertowski, S., Smarz-Widelska, I., & Grywalska, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020647 · Cited by 34
Regulation of microglia phagocytosis and potential involvement of exercise
Li, C., Wang, Y., Xing, Y., Han, J., Zhang, Y., Zhang, A., Hu, J., Hua, Y., & Bai, Y. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.953534 · Cited by 37
The emerging role of brain neuroinflammatory responses in Alzheimer’s disease
AmeliMojarad, M., AmeliMojarad, M., & Cui, X. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1391517 · Cited by 34
“In animal models of Alzheimer’s disease, IL-33 stimulates microglia and protects against A β plaques, despite its association with inflammation (Fu et al., 2016).”
BackgroundBoraschi, D., Italiani, P., Migliorini, P., & Bossù, P. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1128190 · Cited by 38
“In animal models, IL-33 decreases inflammatory responses and improves AD-like pathology (67).”
BackgroundContribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer’s disease
Ishii, A., Pathoulas, J., Omar, O. M., Ge, Y., Yao, A. Y., Pantalena, T., Singh, N., Zhou, J., He, W., Murphy, P. A., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00759-z · Cited by 31
“IL-33 administration into APP/PS1 mice has been shown to reduce soluble Aβ levels and amyloid plaque deposition by promoting the recruitment of microglia for enhancing Aβ phagocytic activity [17].”
Fu, W., Hung, K.-W., Lau, S., Butt, B. W. Y., Yuen, V. W., Fu, G., Chan, I. C. W., Ip, F. C. F., Fu, A. K. Y., & Ip, N. Y. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00600 · Cited by 33
Self-citationLi, Q., Peng, J., Luo, Y., Zhou, J., Li, T., Cao, L. S., Peng, S., Zuo, Z., & Wang, Z. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02521-y · Cited by 36
“As the resident immune cells in brain, microglia may be the first responder to clean Aβ through phagocytosis [49].”
BackgroundKršek, A., Ostojić, L., Zivalj, D., & Batičić, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179695 · Cited by 36
Mast cells initiate the vascular response to contact allergens by sensing cell stress
Hoppe, A., Katsoulis‐Dimitriou, K., Edler, H. J., et al. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.01.036 · Cited by 31
Zong, M.-M., Zhou, Z., Ji, M., Jia, M., Tang, H., & Yang, J. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00293 · Cited by 31
Entanglement of CCR5 and Alzheimer’s Disease
Li, T., & Zhu, J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00209 · Cited by 31
“The distinct subtypes of microglia contribute to the AD course in a diverse manner, and the heterogeneity of pro- and anti-inflammatory timing of microglia is a formidable obstacle (Martin et al., 2010; Heneka Michael et al., 2013; Medeiros et al., 2013; Chakrabarty et al., 2015; Marie-Victoire et al., 2015; Fu et al.…”
BackgroundYeung, S. S.-H., Ho, J. Y. S., & Chang, R. C. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00660-5 · Cited by 32
Impact of TNF and IL-33 Cytokines on Mast Cells in Neuroinflammation
Conti, P., Ronconi, G., Lauritano, D., Mastrangelo, F., Caraffa, A., Gallenga, C. E., Frydas, I., Kritas, S. K., Carinci, F., Gaudelli, F., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063248 · Cited by 32
“• IL-33 modulates microglia in the production of NLRP3 and reduces the production of the cytokines IL-1 and IL-6 [111].”
BackgroundInfluentialMa, X., Wang, Y., Hua, J., Xu, C., Yang, T., Yuan, J., Chen, G., Guo, Z., & Wang, X. (2019) · Science China Chemistry · doi:10.1007/s11426-019-9594-y · Cited by 30
Wu, J., Gao, G., Shi, F., Xie, H., Yang, Q., Liu, D., Qu, S., Qin, H., Zhang, C., Xu, G., et al. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-021-02046-6 · Cited by 28
Discerning the Role of Blood Brain Barrier Dysfunction in Alzheimer’s Disease
Tao, Q., Lin, R.-R., Chen, Y.-H., & Wu, Z. (2022) · Aging and Disease · doi:10.14336/ad.2022.0130-1 · Cited by 34
“IL-33 was confirmed to ameliorate AD pathology and cognitive decline in APP/PS1 mice [111].”
BackgroundWang, Y., Wang, K., Yan, J., Zhou, Q., & Wang, X. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213886 · Cited by 32
New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease
Li, N., Deng, M., Hu, G., Li, N., Yuan, H., & Zhou, Y. (2022) · Biomolecules · doi:10.3390/biom12111722 · Cited by 30
Amelioration of amyloid-β-induced deficits by DcR3 in an Alzheimer’s disease model
Liu, Y., Chen, W.-T., Lin, Y.-Y., Lu, P.-H., Hsieh, S.-L. E., & Cheng, I. H.-J. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0173-0 · Cited by 29
“For example, intracerebral injections of IL4/IL-13 or IL-33 reverse memory deficits and reduce Aβ plaque load in AD mouse models [41, 42].”
Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimers Disease
Nagae, T., & Araki, K. (2016) · Journal of Clinical & Cellular Immunology · doi:10.4172/2155-9899.1000441 · Cited by 28
“(ii) Other members of the IL-1 superfamily, including IL-1 receptor antagonist, IL-18, and IL-33, which are involved in AD pathogenesis [17,60-65].”
BackgroundSian‐Hülsmann, J., & Riederer, P. F. (2024) · Journal of Neural Transmission · doi:10.1007/s00702-023-02723-5 · Cited by 30
Immune and Imaging Correlates of Mild Cognitive Impairment Conversion to Alzheimer’s Disease
Rosa, F. L., Saresella, M., Baglio, F., Piancone, F., Marventano, I., Calabrese, E., Nemni, R., Ripamonti, E., Cabinio, M., & Clerici, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-16754-y · Cited by 26
Augustine, J., Pavlou, S., Harkin, K., Stitt, A. W., Xu, H., & Chen, M. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.050174 · Cited by 27
“…shown to modulate the innate immune response by polarising microglia/macrophages towards an anti-inflammatory phenotype and reducing the expression of proinflammatory genes ( Il1b , Il6 and Nlrp3 ) in the cortices of APP/PS1 mice, an experimental model of Alzheimer ’ s disease (Fu et al., 2016).”
de Campos-Carli, S. M., de Miranda, A. S., Dias, I. C. S., Oliveira, A. D. S., Cruz, B. F., Vieira, É. L. M., Rocha, N. P., Barbosa, I. G., Salgado, J. V., & Teixeira, A. L. (2017) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2017.01.008 · Cited by 28
Avalon Genomics (HK) Limited, S., Yee, A., Tsui, N. B. Y., Chang, Y., Au, C. S., Fok, M., Lau, L. T., Chung, T., Cheng, G. Y.-M., Kwan, R. Y. C., et al. (2018) · Hong Kong Medical Journal · doi:10.12809/hkmj187244 · Cited by 26
Impact of IL-21-associated peripheral and brain crosstalk on the Alzheimer’s disease neuropathology
Agrawal, S., Baulch, J. E., Madan, S., Salah, S., Cheeks, S. N., Krattli, R. P., Subramanian, V. S., Acharya, M. M., & Agrawal, A. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04347-6 · Cited by 25
“It has been reported to be neuroprotective as it inhibits neuronal cell death, enhances cognitive function and phagocytic activity of microglia, and reduces Aβ levels [16].”
BackgroundNeuro-Immuno-Gene- and Genome-Editing-Therapy for Alzheimer’s Disease: Are We There Yet?
Raikwar, S. P., Thangavel, R., Dubova, I., Ahmed, M. E., Selvakumar, G. P., Kempuraj, D., Zaheer, S. A., Iyer, S. S., & Zaheer, A. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180422 · Cited by 27
“Independent studies have shown that IL-33 transcript and protein levels are reduced in the brains of late onset AD patients as compared to healthy individuals [72, 73].”
BackgroundUsing blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification
Zhong, H., Zhou, X., Uhm, H., Jiang, Y., Cao, H., Chen, Y., Mak, T. T. W., Lo, R. M. N., Wong, B. W. Y., Cheng, E. Y. L., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13691 · Cited by 25
“70,71 74 Insummary,ourcomprehensiveanalysisofthebloodtranscriptome inpatientswithADrevealskeymolecularphenotypes,includinggenes, modules, pathways, and subtypes of blood cells, that may be closely associated with AD pathogenesis and progression.”
BackgroundSelf-citationIL-33 suppresses GSK-3β activation through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway
Nishizaki, T. (2018) · Heliyon · doi:10.1016/j.heliyon.2018.e00971 · Cited by 25
“IL-33 reduces soluble Ab levels and amyloid plaque deposition by promoting microglia-engaged phagocytosis of Ab [22].”
BackgroundLi, X., Wang, X., Feng, X., Shao, M., Liu, W., Ma, Q., Wang, E., Chen, J., & Shao, B. (2019) · Brain and Behavior · doi:10.1002/brb3.1369 · Cited by 25
“Fu et al. (2016) im‐ plied that IL‐33 played a neuroprotective role and was a potential therapeutic approach for Alzheimer disease.”
BackgroundKurmann, L., Okoniewski, M. J., Ogunshola, O. O., Leeners, B., Imthurn, B., & Dubey, R. K. (2021) · Cells · doi:10.3390/cells10040963 · Cited by 26
“With regard to IL-1-R4 (also called ST2), which is a decoy receptor for IL-33 and blocks its function [46,47], upregulation in its expression may protect BBB against IL-33 mediated EC insult, activation and microglia-mediated neuroinflammation.”
BackgroundLin, L., Li, Y., Liu, M., Li, Q., Liu, Q., & Li, R. (2020) · Aging · doi:10.18632/aging.102707 · Cited by 24
Cheng, J.-L., Tan, C., Liu, H.-Y., Han, D., & Liu, Z. (2023) · World Journal of Psychiatry · doi:10.5498/wjp.v13.i9.607 · Cited by 24
The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies
Karahan, H., Smith, D. C., Kim, B., McCord, B., Mantor, J., John, S. K., Al-Amin, M. M., Dabin, L. C., & Kim, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1102530 · Cited by 20
“Furthermore, IL-33 administration ameliorated memory deficits and reduced Ab deposition in the APP/PS1 mouse model (54).”
BackgroundBiomarkers Utility: At the Borderline between Cardiology and Neurology
Chetran, A., Stafie, C. S., Mitu, O., Ciobanu, E. C., Iliescu-Halițchi, D., Costache, A. D., Bobric, C., Troase, R., Mitu, I., Huzum, B., et al. (2021) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd8110139 · Cited by 25
“The pathogenesis of Alzheimer disease may involve an impaired IL33/ST2 signaling, with the inhibition of β amyloid phagocytosis and clearance by microglia, which promotes chronic neuroinflammation and amyloid plaque deposition [112].”
BackgroundMalter, J. S. (2022) · Translational research · doi:10.1016/j.trsl.2022.09.003 · Cited by 23
Montoliu‐Gaya, L., Güell‐Bosch, J., Esquerda-Canals, G., Roda, A. R., Serra-Mir, G., Lope‐Piedrafita, S., Sánchez‐Quesada, J. L., & Villegas, S. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.07.012 · Cited by 23
Nascimento‐dos‐Santos, G., Teixeira‐Pinheiro, L. C., da Silva‐Junior, A. J., de Carvalho, L. R. P., Mesentier-Louro, L. A., Hauswirth, W. W., Méndez‐Otero, R., Santiago, M. F., & Petrs‐Silva, H. (2019) · Gene Therapy · doi:10.1038/s41434-019-0089-0 · Cited by 22
Zinc utilization by microglia in Alzheimer’s disease
Shippy, D. C., Oliai, S. F., & Ulland, T. K. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107306 · Cited by 25
What Is the Role of Cytokines in Synaptic Transmission?
Benarroch, E. E. (2024) · Neurology · doi:10.1212/wnl.0000000000209928 · Cited by 21
Wang, K., Fernandez-Escobar, A., Han, S., Zhu, P., Wang, J., & Sun, Y. S. (2016) · BioMed Research International · doi:10.1155/2016/7810196 · Cited by 21
“More importantly, reduction of IL-1β and IL-6 is associated with better cognitive performances in ADmice [34].”
BackgroundInfluentialYuan, X., Tang, R., Jia, Z., Chen, Y., Liu, J., & Liu, Y. (2023) · Chemical Engineering Journal · doi:10.1016/j.cej.2023.142679 · Cited by 22
Knowledge mapping and research trends of IL-33 from 2004 to 2022: a bibliometric analysis
Jin, J., Wan, Y., Shu, Q., Liu, J., & Lai, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1158323 · Cited by 21
“He and his team have also proposed a relationship between IL-33 and diseases such as sepsis (38), oncological chemotherapy (39), Alzheimer’s disease (40), and cerebral malaria (41, 42), and suggest that IL-33 is a double-edged sword, the rational regulation of which may have considerable potential therapeutic effects.”
BackgroundWang, Z., Xiong, L., Wan, W., Duan, L., Bai, X., & Zu, H. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00032 · Cited by 22
“We next investigated the effects of BMP9 on APP/PS1 mouse associative learning and memory using a standard conditioned fear memory paradigm (Fu et al., 2016).”
MethodThe rise of astrocytes: are they guardians or troublemakers of the brain disorder?
Kim, H. Y., Kim, S., Akaydin, A. N., Kim, S. S., Hyeon, S. J., Lee, J.-H., & Ryu, H. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01627-6 · Cited by 28
“Similarly, cytokines including IL-10, IL-33 and interferon-β have been studied for their potential to suppress proin fl ammatory cytokine production and enhance memory 136 .”
Lau, S., Fu, A. K. Y., & Ip, N. Y. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15933 · Cited by 21
Self-citationLau, J. K. Y., Tian, M., Shen, Y., Lau, S., Fu, W., Fu, A. K. Y., & Ip, N. Y. (2021) · Scientific Reports · doi:10.1038/s41598-021-83932-4 · Cited by 19
Self-citationTsay, H.-J., Liu, H., Kuo, Y., Chiu, C.-S., Liang, C.-C., Chung, C.-W., Chen, C., Chen, Y.-P., & Shiao, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910413 · Cited by 19
IL-33 gene variants and protein expression in pediatric Tunisian asthmatic patients
Charrad, R., Kaabachi, W., Berraïes, A., Hamzaoui, K., & Hamzaoui, A. (2017) · Cytokine · doi:10.1016/j.cyto.2017.09.028 · Cited by 19
Brain interleukins and Alzheimer’s disease
Abdelhamed, H. G., Hassan, A. A., Sakraan, A., Al-Deeb, R. T., Mousa, D. M., Ezz, H. S. A., Noor, N. A., Khadrawy, Y. A., & Radwan, N. M. (2025) · Metabolic Brain Disease · doi:10.1007/s11011-025-01538-5 · Cited by 20
“In an animal study using AD mouse models, peripheral IL-33 administration was shown to decrease the levels of soluble Aβ and the deposition of amyloid plaque and reverse the deterioration in synaptic plasticity and cognitive functions (Fu et al. 2016).”
Chen, Y., Xu, J., Zhou, X., Liu, S., Zhang, Y., Ma, S., Fu, A. K. Y., Ip, N. Y., & Chen, Y. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00190 · Cited by 18
Self-citation
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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