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Cited by 105Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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Cromolyn Reduces Levels of the Alzheimer’s Disease-Associated Amyloid β-Protein by Promoting Microglial Phagocytosis

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Zhang, Can, Griciuc, Ana, Hudry, Eloise, Wan, Yu, Quinti, Luisa, Ward, Joseph, Forte, Angela M., Shen, Xunuo, Ran, ChongZhao, Elmaleh, David R., Tanzi, Rudolph E.·2018·Scientific Reports
DOI 10.1038/s41598-018-19641-2PMC PMC5773545
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Abstract

Amyloid-beta protein (Aβ) deposition is a pathological hallmark of Alzheimer’s disease (AD). Aβ deposition triggers both pro-neuroinflammatory microglial activation and neurofibrillary tangle formation. Cromolyn sodium is an asthma therapeutic agent previously shown to reduce Aβ levels in transgenic AD mouse brains after one-week of treatment. Here, we further explored these effects as well as the mechanism of action of cromolyn, alone, and in combination with ibuprofen in APP Swedish-expressing Tg2576 mice. Mice were treated for 3 months starting at 5 months of age, when the earliest stages of β-amyloid deposition begin. Cromolyn, alone, or in combination with ibuprofen, almost completely abolished longer insoluble Aβ species, i.e. Aβ40 and Aβ42, but increased insoluble Aβ38 levels. In addition to its anti-aggregation effects on Aβ, cromolyn, alone, or plus ibuprofen, but not ibuprofen alone, increased microglial recruitment to, and phagocytosis of β-amyloid deposits in AD mice. Cromolyn also promoted Aβ42 uptake in microglial cell-based assays. Collectively, our data reveal robust effects of cromolyn, alone, or in combination with ibuprofen, in reducing aggregation-prone Aβ levels and inducing a neuroprotective microglial activation state favoring Aβ phagocytosis versus a pro-neuroinflammatory state. These findings support the use of cromolyn, alone, or with ibuprofen, as a potential AD therapeutic.

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Figure 1 Cromolyn and/or ibuprofen robustly affected Aβ levels and Aβ42:Aβ40 ratios in brain TBS-insoluble samples. (A,B) MesoScale Aβ-triplex analyses were applied to brain TBS-insoluble samples. Differences in Aβ levels (A) and Aβ(42:40) ratios (B) were assessed comparing various treatment groups to vehicle. Mean ± SEM; n ≥ 8 (Table 1); *p < 0.05; ***p< 0.001 (vs. vehicle); one-way ANOVA with Dunnett’s multiple comparison test. Abbreviations: Aβ(42:40): Aβ42: Aβ40.
Figure 1 Cromolyn and/or ibuprofen robustly affected Aβ levels and Aβ42:Aβ40 ratios in brain TBS-insoluble samples. (A,B) MesoScale Aβ-triplex analyses were applied to brain TBS-insoluble samples. Differences in Aβ levels (A) and Aβ(42:40) ratios (B) were assessed comparing various treatment groups to vehicle. Mean ± SEM; n ≥ 8 (Table 1); *p < 0.05; ***p< 0.001 (vs. vehicle); one-way ANOVA with Dunnett’s multiple comparison test. Abbreviations: Aβ(42:40): Aβ42: Aβ40.CC BY · PubMed Central
Figure 2 High dose cromolyn and combined high dose cromolyn with ibuprofen upregulated Aβ levels in brain TBS-soluble samples; High dose cromolyn elevated Aβ42:Aβ40 ratios in brain TBS-soluble samples. (A,B) MesoScale Aβ-triplex analyses were applied to brain TBS-soluble samples. Differences in Aβ levels (A) and Aβ42:Aβ40 ratios (B) were analyzed comparing various treatment groups to vehicle. Mean ± SEM (normalized to vehicle); n ≥ 8 (Table 1); *p < 0.05; **p < 0.01 (vs. vehicle); one-way ANOVA with Dunnett’s multiple comparison test.
Figure 2 High dose cromolyn and combined high dose cromolyn with ibuprofen upregulated Aβ levels in brain TBS-soluble samples; High dose cromolyn elevated Aβ42:Aβ40 ratios in brain TBS-soluble samples. (A,B) MesoScale Aβ-triplex analyses were applied to brain TBS-soluble samples. Differences in Aβ levels (A) and Aβ42:Aβ40 ratios (B) were analyzed comparing various treatment groups to vehicle. Mean ± SEM (normalized to vehicle); n ≥ 8 (Table 1); *p < 0.05; **p < 0.01 (vs. vehicle); one-way ANOVA with Dunnett’s multiple comparison test.CC BY · PubMed Central
Figure 3 Low dose cromolyn increased plasma Aβ42:Aβ40 ratios. (A,B). MesoScale Aβ-triplex analyses were applied to plasma samples. Differences in Aβ levels (A) and Aβ42:Aβ40 ratios (B) in plasma were analyzed comparing various treatment groups to vehicle. Mean ± SEM; n ≥ 8 (Table 1); *p < 0.05 (vs. vehicle), one-way ANOVA with Dunnett’s multiple comparison test.
Figure 3 Low dose cromolyn increased plasma Aβ42:Aβ40 ratios. (A,B). MesoScale Aβ-triplex analyses were applied to plasma samples. Differences in Aβ levels (A) and Aβ42:Aβ40 ratios (B) in plasma were analyzed comparing various treatment groups to vehicle. Mean ± SEM; n ≥ 8 (Table 1); *p < 0.05 (vs. vehicle), one-way ANOVA with Dunnett’s multiple comparison test.CC BY · PubMed Central
Figure 4 Cromolyn and/or ibuprofen did not significantly influence the levels of Aβ and Aβ42:Aβ40 ratios in mouse CSF samples. (A,B) MesoScale Aβ-triplex analyses were applied to CSF samples. Differences in Aβ levels (A) and Aβ42:Aβ40 ratios (B) were analyzed comparing various treatment groups to vehicle. Mean ± SEM; n ≥8 (Table 1); one-way ANOVA with Dunnett’s multiple comparison test.
Figure 4 Cromolyn and/or ibuprofen did not significantly influence the levels of Aβ and Aβ42:Aβ40 ratios in mouse CSF samples. (A,B) MesoScale Aβ-triplex analyses were applied to CSF samples. Differences in Aβ levels (A) and Aβ42:Aβ40 ratios (B) were analyzed comparing various treatment groups to vehicle. Mean ± SEM; n ≥8 (Table 1); one-way ANOVA with Dunnett’s multiple comparison test.CC BY · PubMed Central
Figure 5 Cromolyn, but not ibuprofen, increased microglial activity in AD mice. (A,B) Cromolyn increased microglial activity related to β-amyloid deposits in mice. Iba1-positive microglial processes (red) colocalizing with β-amyloid deposits (green) were showed (A) and quantified (B). We represented pictures of β-amyloid deposits and Iba-1 positive microglia for the highest concentration only from each drug treatment group. Mean ± SEM; *p < 0.05, **p < 0.01, one-way ANOVA with post-hoc Tukey’s multiple comparison test. (C) Cromolyn, but not ibuprofen, promoted Aβ42 uptake in BV2 microglial cell culture studies. BV2 microglial cell cultures were treated with cromolyn and/or ibuprofen (10 μM, 100 μM, 1 mM) for 16 hours. Afterwards, cells were incubated with soluble Aβ42 and the compounds for additional 3 hours. After incubation, cells were collected for Aβ ELISA analysis. BV2 microglial cells treated with cromolyn (100 μM, 1 mM), and with combined cromolyn and ibuprofen (100 μM, 1 mM for each compound) exhibited increased Aβ42 uptake levels relative to BV2 microglia treated with vehicle. Mean ± SEM; n = 3; **p < 0.01, ***p < 0.001, one-way ANOVA post-hoc Tukey’s multiple comparison test.
Figure 5 Cromolyn, but not ibuprofen, increased microglial activity in AD mice. (A,B) Cromolyn increased microglial activity related to β-amyloid deposits in mice. Iba1-positive microglial processes (red) colocalizing with β-amyloid deposits (green) were showed (A) and quantified (B). We represented pictures of β-amyloid deposits and Iba-1 positive microglia for the highest concentration only from each drug treatment group. Mean ± SEM; *p < 0.05, **p < 0.01, one-way ANOVA with post-hoc Tukey’s multiple comparison test. (C) Cromolyn, but not ibuprofen, promoted Aβ42 uptake in BV2 microglial cell culture studies. BV2 microglial cell cultures were treated with cromolyn and/or ibuprofen (10 μM, 100 μM, 1 mM) for 16 hours. Afterwards, cells were incubated with soluble Aβ42 and the compounds for additional 3 hours. After incubation, cells were collected for Aβ ELISA analysis. BV2 microglial cells treated with cromolyn (100 μM, 1 mM), and with combined cromolyn and ibuprofen (100 μM, 1 mM for each compound) exhibited increased Aβ42 uptake levels relative to BV2 microglia treated with vehicle. Mean ± SEM; n = 3; **p < 0.01, ***p < 0.001, one-way ANOVA post-hoc Tukey’s multiple comparison test.CC BY · PubMed Central

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Authors
Zhang, C., Griciuc, A., Hudry, E., Wan, Y., Quinti, L., Ward, J., Forte, A. M., Shen, X., Ran, C., Elmaleh, D. R., & Tanzi, R. E.
Affiliations
Harvard University (US)
Corresponding author
Tanzi, Rudolph E.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-01-18
Volume
8
Issue
1
Pages
1144-1144
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-19641-2
PMC
PMC5773545
OpenAlex
W2782619707
Cited by
99
References
32
Citations by year
2026: 8 · 2025: 11 · 2024: 9 · 2023: 15 · 2022: 15 · 2021: 16 · 2020: 14 · 2019: 6 · 2018: 3
FWCI
6.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Cure Alzheimer's Fund
  • National Institute on Aging (R00AG047336)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
disodium cromoglycate, amyloid-beta, Alzheimer's disease, microglial phagocytosis, ibuprofen, amyloid-beta aggregation, amyloid-beta 42, Aβ40, microglial recruitment, neuroinflammation, Tg2576 mice, anti-aggregation therapy
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Cromolyn Sodium, Drug Combinations, Humans, Ibuprofen, Male, Mice, Transgenic, Neurons, Peptide Fragments, Phagocytosis, Gene Expression, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Neuroprotective Agents, Anti-Asthmatic Agents, Transgenes, Mice, Drug Repositioning

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