CoChat
Sign Up
Cited by 118Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease

Open access
Taubes, Alice, Nova, Phil, Zalocusky, Kelly A., Kosti, Idit, Bicak, Mesude, Zilberter, Misha Y., Hao, Yanxia, Yoon, Seo Yeon +18 more·2021·Nature Aging
DOI 10.1038/s43587-021-00122-7PMC PMC9514594
Open this paper in CoChat — free account

Abstract

The evident genetic, pathological, and clinical heterogeneity of Alzheimer's disease (AD) poses challenges for traditional drug development. We conducted a computational drug repurposing screen for drugs to treat apolipoprotein (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Aβ accumulation rescued electrophysiological, pathological, or cognitive deficits. Single-nucleus RNA-sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in apoE4-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s43587-021-00122-7

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • There are more lipid-droplet-positive microglia in J20/APOE3 and J20/APOE4 Alzheimer's disease mouse models compared to age-matched wild-type mice.

    “Mirroring these observations in the human AD tissue, there are more LD+ microglia in the J20/APOE3 and J20/APOE4 models of AD15 compared to age-matched wild-type mice”

    From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [15]

    The Methods (Mice; page unavailable) identify J20/E3-KI, J20/E4-KI, and wild-type mice. The Results on J20/E4-KI neurons and glia discuss microglial gene expression, but neither passage reports counts of lipid-droplet-positive microglia compared with age-matched wild-type mice. Searches for “lipid droplets,” “LD+ microglia,” and the model comparison found no passage addressing that outcome. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 66 · Cited by 118

Research works printed but not linked: 54

  1. [1]Golde TE, Schneider LS & Koo EH Anti-Aβ therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron 69, 203– 213 (2011). 21262461 PMC3058906
  2. [3]Liu CC, Kanekiyo T, Xu H & Bu G Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9, 106– 118 (2013). 23296339 PMC3726719
  3. [5]Mahley RW & Huang Y Apolipoprotein E sets the stage: response to injury triggers neuropathology. Neuron 76, 871– 885 (2012). 23217737 PMC4891195
  4. [6]Corder EH, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921– 923 (1993). 8346443
  5. [7]Barnes EE & Yaffe K Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med 353, 951– 952 (2005). 16135844
  6. [8]Marchant NL, King SL, Tabet N & Rusted JM Positive effects of cholinergic stimulation favor young APOE epsilon4 carriers. Neuropsychopharmacology 35, 1090– 1096 (2010). 20072115 PMC3055410
  7. [9]Salloway S, Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N. Engl. J. Med 370, 322– 333 (2014). 24450891 PMC4159618
  8. [10]Cheng F, Prediction of drug-target interactions and drug repositioning via network-based inference. PLoS Comput. Biol 8, e1002503 (2012). 22589709 PMC3349722
  9. [11]Csermely P, Korcsmaros T, Kiss HJ, London G & Nussinov R Structure and dynamics of molecular network: a novel paradigm of drug discovery: a comprehensive review. Pharmacol Ther 138, 333– 408 (2013). 23384594 PMC3647006
  10. [12]Sirota M, Discovery and preclinical validation of drug indications using compendia of public gene expression data. Sci. Transl. Med 3, 96ra77 (2011). PMC3502016 21849665
  11. [13]Chen B, Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells In Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling. Gastroenterology 152, 2022– 2036 (2017). 28284560 PMC5447464
  12. [14]Chen B & Butte AJ Leveraging big data to transform target selection and drug discovery. Clin. Pharmacol. Ther 99, 285– 297 (2016). 26659699 PMC4785018
  13. [15]Cai X, Chen Y, Gao Z & Xu R Explore Small Molecule-induced Genome-wide Transcriptional Profiles for Novel Inflammatory Bowel Disease Drug. AMIA Jt. Summits. Transl. Sci. Proc 2016, 22– 31 (2016). 27570643 PMC5001780
  14. [16]Lamb J, The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929– 1935 (2006). 17008526
  15. [19]Ritchie ME, limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015). 25605792 PMC4402510
  16. [20]Chen B, Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets. Nat Commun 8, 16022 (2017). 28699633 PMC5510182
  17. [21]Gharaylou Z, A Preliminary Study Evaluating the Safety and Efficacy of Bumetanide, an NKCC1 Inhibitor, in Patients with Drug-Resistant Epilepsy. CNS drugs 33, 283– 291 (2019). 30784026
  18. [22]Goubert E, Bumetanide prevents brain trauma-induced depressive-like behavior. Front. Mol. Neurosci 12, 12 (2019). 30804751 PMC6370740
  19. [23]Lemonnier E, A randomised controlled trial of bumetanide in the treatment of autism in children. Transl. psychiatry 2, e202 (2012). 23233021 PMC3565189
  20. [24]Lemonnier E, Lazartigues A & Ben-Ari Y Treating schizophrenia with the diuretic bumetanide: a case report. Clin. neuropharmacol 39, 115– 117 (2016). 26966887
  21. [25]Lemonnier E, Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl. psychiatry 7, e1056 (2017). 28291262 PMC5416661
  22. [26]Rahmanzadeh R, Effect of co-administration of bumetanide and phenobarbital on seizure attacks in temporal lobe epilepsy. Basic Clin. neurosci 9, 408– 416 (2018). 30719255 PMC6359685
  23. [27]Sivakumaran S & Maguire J Bumetanide reduces seizure progression and the development of pharmacoresistant status epilepticus. Epilepsia 57, 222– 232 (2016). 26659482 PMC5487491
  24. [28]Zhao N, Alzheimer’s Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways. Neuron 106, 727– 742 e726 (2020). 32199103 PMC7388065
  25. [29]Najm R, Jones EA & Huang Y Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease. Mol. Neurodegener 14, 24 (2019). 31186040 PMC6558779
  26. [30]Milior G, Electrophysiological properties of CA1 pyramidal neurons along the longitudinal axis of the mouse hippocampus. Sci. Rep 6, 38242 (2016). 27922053 PMC5138623
  27. [31]Bliss TV & Collingridge GL A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31– 39 (1993). 8421494
  28. [32]Selkoe DJ Alzheimer’s disease is a synaptic failure. Science 298, 789– 791 (2002). 12399581
  29. [35]Knoferle J, Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice. J Neurosci 34, 14069– 14078 (2014). 25319703 PMC4198545
  30. [36]Mucke L, High-level neuronal expression of Ab1–42 in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation. J. Neurosci 20, 4050– 4058 (2000). 10818140 PMC6772621
  31. [37]Bien-Ly N, Gillespie AK, Walker D, Yoon SY & Huang Y Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J. Neurosci 32, 4803– 4811 (2012). 22492035 PMC3433173
  32. [39]Lennon MJ, Makkar SR, Crawford JD & Sachdev PS Midlife Hypertension and Alzheimer’s Disease: A Systematic Review and Meta-Analysis. J Alzheimers Dis 71, 307– 316 (2019). 31381518
  33. [40]Ho J, Tumkaya T, Aryal S, Choi H & Claridge-Chang A Moving beyond P values: data analysis with estimation graphics. Nat Methods 16, 565– 566 (2019). 31217592
  34. [41]Kharod SC, Kang SK & Kadam SD Off-Label Use of Bumetanide for Brain Disorders: An Overview. Front. Neurosci 13, 310 (2019). 31068771 PMC6491514
  35. [42]Puskarjov M, Kahle KT, Ruusuvuori E & Kaila K Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures. Epilepsia 55, 806– 818 (2014). 24802699 PMC4284054
  36. [43]Töpfer M, Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy. Eur. J. Neurosci 39, 673– 687 (2014). 24251546
  37. [44]Gharaylou Z, Longitudinal effects of bumetanide on neuro-cognitive functioning in drug-resistant epilepsy. Front. Neurol 10, 483 (2019). 31133976 PMC6517515
  38. [47]Griswold AJ, Increased APOE epsilon4 expression is associated with the difference in Alzheimer’s disease risk from diverse ancestral backgrounds. Alzheimers Dement 17, 1179– 1188 (2021). 33522086 PMC8843031
  39. [48]Caselli RJ Obstructive sleep apnea, apolipoprotein E e4, and mild cognitive impairment. Sleep Med. 9, 816– 817 (2008). 18226961 PMC2668696
  40. [49]Drogos L, Evidence of association between sleep quality and APOE ε4 in healthy older adults: A pilot study. Neurology 87, 1836– 1842 (2016). 27777343 PMC5089524
  41. [50]Tranah GJ, APOEε4 and slow wave sleep in older adults. PloS One 13, e0191281 (2018). 29370207 PMC5784964
  42. [51]Gozal D, Capdevila OS, Kheirandish-Gozal L & Crabtree VM APOE epsilon 4 allele, cognitive dysfunction, and obstructive sleep apnea in children. Neurology 69, 243– 249 (2007). 17636061
  43. [52]Listos J, The Mechanisms Involved in Morphine Addiction: An Overview. Int J Mol Sci 20(2019). PMC6747116 31484312
  44. [53]Falcon E & McClung CA A role for the circadian genes in drug addiction. Neuropharmacology 56 Suppl 1, 91– 96 (2009). 18644396 PMC2635341
  45. [54]Hamanaka H, Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice. Hum. Mol. Genet 9, 353– 361 (2000). 10655544
  46. [55]Sullivan PM, Mace BE, Maeda N & Schmechel DE Marked regional differences of brain human apolipoprotein E expression in targeted replacement mice. Neuroscience 124, 725– 733 (2004). 15026113
  47. [56]Workman C, A new non-linear normalization method for reducing variability in DNA microarray experiments. Genome Biol 3, research0048.0041–0048.0016 (2002). PMC126873 12225587
  48. [57]Lui JH, Radial glia require PDGFD-PDGFRbeta signalling in human but not mouse neocortex. Nature 515, 264– 268 (2014). 25391964 PMC4231536
  49. [58]Raju CS, Secretagogin is expressed by developing neocortical GABAergic neurons in humans but not mice and increases neurite arbor size and complexity. Cereb Cortex 28, 1946– 1958 (2018). 28449024 PMC6019052
  50. [59]Butler A, Hoffman P, Smibert P, Papalexi E & Satija R Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 36, 411– 420 (2018). 29608179 PMC6700744
  51. [61]Rosenberg AB, Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding. Science 360, 176– 182 (2018). 29545511 PMC7643870
  52. [62]Dijk D.v., Recovering gene interactions from single-cell data using data diffusion. Cell 174, 716– 729 (2018). 29961576 PMC6771278
  53. [63]Dobin A, STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15– 21 (2013). 23104886 PMC3530905
  54. [64]Liao Y, Smyth GK & Shi W featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923– 930 (2014). 24227677

Authors
Taubes, A., Nova, P., Zalocusky, K. A., Kosti, I., Bicak, M., Zilberter, M. Y., Hao, Y., Yoon, S. Y., Oskotsky, T., Pineda, S., Chen, B., Aery Jones, E. A., Choudhary, K., Grone, B., Balestra, M. E., Chaudhry, F., Paranjpe, I., De Freitas, J., Koutsodendris, N., Chen, N., Wang, C., Chang, W., An, A., Glicksberg, B. S., Sirota, M., & Huang, Y.
Affiliations
  • Gladstone Institutes (US)
  • University of California, San Francisco (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
  • Sirota, Marina
  • Huang, Yadong
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2021-10-11
Volume
1
Issue
10
Pages
932-947
ISSN
2662-8465 (ISSN-L)
DOI
10.1038/s43587-021-00122-7
PMC
PMC9514594
OpenAlex
W3205064505
Cited by
118
References
66
Citations by year
2026: 20 · 2025: 19 · 2024: 26 · 2023: 22 · 2022: 27 · 2021: 3
FWCI
13.35
Type
journal article
Language
en
Update notices
correction (2021-11-12)
Open access
Licence
Locations
  • Nature Aging (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (1F31AG058439, AG057683, 1F31AG057150, AG048017)
  • U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (TR001743)
  • U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (ES028047)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
bumetanide, drug repurposing, Alzheimer's disease, APOE ε4, computational drug screening, Connectivity Map, gene expression signatures, amyloid-beta, single-nucleus RNA sequencing, iPSC-derived neurons, electronic health records, cognitive impairment
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Bumetanide, Humans, Mice, Transgenic, Amyloid beta-Peptides, Mice, Apolipoprotein E4, Drug Repositioning

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.

Statistics and arithmetic are recomputed, not judged.

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

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

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