Age and Alzheimer’s disease gene expression profiles reversed by the glutamate modulator riluzole
Open accessAbstract
Alzheimer's disease (AD) and age-related cognitive decline represent a growing health burden and involve the hippocampus, a vulnerable brain region implicated in learning and memory. To understand the molecular effects of aging on the hippocampus, this study characterized the gene expression changes associated with aging in rodents using RNA-sequencing (RNA-seq). The glutamate modulator, riluzole, which was recently shown to improve memory performance in aged rats, prevented many of the hippocampal age-related gene expression changes. A comparison of the effects of riluzole in rats against human AD data sets revealed that many of the gene changes in AD are reversed by riluzole. Expression changes identified by RNA-Seq were validated by qRT-PCR open arrays. Riluzole is known to increase the glutamate transporter EAAT2's ability to scavenge excess glutamate, regulating synaptic transmission. RNA-seq and immunohistochemistry confirmed an increase in EAAT2 expression in hippocampus, identifying a possible mechanism underlying the improved memory function after riluzole treatment.
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Downregulation of KCNIP3 in the brains of individuals with AD is associated with memory and learning.
“Downregulation of KCNIP3 in the brains of individuals with AD is associated with memory and learning (63).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [63]
The Results section reports that several genes are diminished in AD tissue, and the Discussion links some of those genes to learning and memory. Neither section identifies KCNIP3 or addresses whether its downregulation is associated with learning and memory; searches for KCNIP3 and its alternative names found no matching passage in our copy. (LLM, conf=0.73)
Experimental — accuracy not yet measuredA comparison of the effects of riluzole in rats against human Alzheimer's disease data sets revealed that many of the gene changes in Alzheimer's disease are reversed by riluzole.
“Moreover, a comparison of the effects of riluzole in rats against human AD data sets revealed that many of the gene changes in Alzheimer's Disease (AD) are reversed by riluzole.”
From Neurobiological and Systemic Effects of Chronic Stress (2017) · cites this paper as [55]
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Neurobiological and Systemic Effects of Chronic Stress
McEwen, B. S. (2017) · Chronic Stress · doi:10.1177/2470547017692328 · Cited by 1,059 · see citing works
“Moreover, a comparison of the effects of riluzole in rats against human AD data sets revealed that many of the gene changes in Alzheimer’s Disease (AD) are reversed by riluzole.(55)”
BackgroundSelf-citationAmino acid transporters revisited: New views in health and disease
Kandasamy, P., Gyimesi, G., Kanai, Y., & Hediger, M. A. (2018) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2018.05.003 · Cited by 484 · see citing works
Pajarillo, E. A. B., Rizor, A., Lee, J., Aschner, M., & Lee, E.-S. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.03.002 · Cited by 477 · see citing works
Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration.
Andersen, J. V., Markussen, K., Jakobsen, E., Schousboe, A., Waagepetersen, H., Rosenberg, P., & Aldana, B. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108719 · Cited by 331 · see citing works
Andersen, J. V., Schousboe, A., & Verkhratsky, A. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102331 · Cited by 259 · see citing works
The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders
Sanacora, G., Yan, Z., & Popoli, M. (2022) · Nature Reviews Neuroscience · doi:10.1038/s41583-021-00540-x · Cited by 197 · see citing works
Gąsiorowska, A., Wydrych, M., Drapich, P., Zadrożny, M., Steczkowska, M., Niewiadomski, W., & Niewiadomska, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.654931 · Cited by 192 · see citing works
Astrocyte senescence promotes glutamate toxicity in cortical neurons
Limbad, C., Oron, T. R., Alimirah, F., Davalos, A. R., Tracy, T. E., Gan, L., Desprez, P.-Y., & Campisi, J. (2020) · PLOS ONE · doi:10.1371/journal.pone.0227887 · Cited by 183 · see citing works
Reactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer’s disease
Price, B. R., Johnson, L. A., & Norris, C. M. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101335 · Cited by 173 · see citing works
The Regulation of Astrocytic Glutamate Transporters in Health and Neurodegenerative Diseases
Todd, A., & Hardingham, G. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249607 · Cited by 169 · see citing works
The Neuroprotective Effects of Astaxanthin: Therapeutic Targets and Clinical Perspective
Fakhri, S., Aneva, I. Y., Farzaei, M. H., & Sobarzo‐Sánchez, E. (2019) · Molecules · doi:10.3390/molecules24142640 · Cited by 166 · see citing works
Redefining neuroendocrinology: Epigenetics of brain-body communication over the life course
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Self-citationClark, I. A., & Vissel, B. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0708-2 · Cited by 123 · see citing works
Kazim, S. F., Seo, J. H., Bianchi, R., Larson, C. S., Sharma, A., Wong, R. K. S., Gorbachev, K., & Pereira, A. C. (2021) · eNeuro · doi:10.1523/eneuro.0418-20.2020 · Cited by 113 · see citing works
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Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders
Ratner, M. H., Kumaresan, V., & Farb, D. H. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00169 · Cited by 96 · see citing works
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Self-citationEarly Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review
Lemche, E. (2018) · Current Genomics · doi:10.2174/1389202919666171229145156 · Cited by 82 · see citing works
Lin, C., Yang, H.-T., & Lane, H. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.172760 · Cited by 79 · see citing works
Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming
Sun, Z., Kwon, J.-S., Ren, Y., Chen, S., Walker, C. K., Lu, X., Cates, K., Karahan, H., Sviben, S., Fitzpatrick, J. A. J., et al. (2024) · Science · doi:10.1126/science.adl2992 · Cited by 77 · see citing works
“Downregulation of KCNIP3 in the brains of individuals with AD is associated with memory and learning (63).”
Cheng, Z., Zhou, H., Sherva, R., Farrer, L. A., Kranzler, H. R., & Gelernter, J. E. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.12.016 · Cited by 72 · see citing works
Okamoto, M., Gray, J. D., Larson, C. S., Kazim, S. F., Soya, H., McEwen, B. S., & Pereira, A. C. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0201-z · Cited by 71 · see citing works
Self-citationFriend or Foe? Defining the Role of Glutamate in Aging and Alzheimer’s Disease
Cox, M. F., Hascup, E. R., Bartke, A., & Hascup, K. N. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.929474 · Cited by 70 · see citing works
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Drug repurposing for Alzheimer’s disease and other neurodegenerative disorders
Cummings, J. L., Zhou, Y., Stone, A. V., Cammann, D., Tonegawa‐Kuji, R., Cacho, J. R. F., & Cheng, F. (2025) · Nature Communications · doi:10.1038/s41467-025-56690-4 · Cited by 61 · see citing works
Hormones and behavior and the integration of brain-body science
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Gene Therapy Strategies Targeting Aging-Related Diseases
Yu, J., Li, T., & Zhu, J. (2022) · Aging and Disease · doi:10.14336/ad.2022.00725 · Cited by 51 · see citing works
Influence of glutamatergic and GABAergic neurotransmission on obstructive sleep apnea
Kaczmarski, P., Sochal, M., Strzelecki, D., Białasiewicz, P., & Gabryelska, A. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1213971 · Cited by 52 · see citing works
Riluzole: a therapeutic strategy in Alzheimer’s disease by targeting the WNT/β-catenin pathway
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Stress and Alzheimer’s disease: A senescence link?
Lyons, C. E., & Bartolomucci, A. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.05.010 · Cited by 47 · see citing works
Cell type-specific potential pathogenic genes and functional pathways in Alzheimer’s Disease
Wang, X., & Li, L. (2021) · BMC Neurology · doi:10.1186/s12883-021-02407-1 · Cited by 46 · see citing works
Sulfur-containing therapeutics in the treatment of Alzheimer’s disease
Zhu, H., Dronamraju, V., Xie, W., & More, S. S. (2021) · Medicinal Chemistry Research · doi:10.1007/s00044-020-02687-1 · Cited by 45 · see citing works
Sakakibara, Y., Sekiya, M., Fujisaki, N., Quan, X., & Iijima, K. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007196 · Cited by 41 · see citing works
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Reversal of Age-Related Neuronal Atrophy by α5-GABAA Receptor Positive Allosteric Modulation
Prévot, T. D., Sumitomo, A., Tomoda, T., Knutson, D. E., Li, G., Mondal, P., Banasr, M., Cook, J. M., & Sibille, E. L. (2020) · Cerebral Cortex · doi:10.1093/cercor/bhaa310 · Cited by 38 · see citing works
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Zhang, J., Qiao, Y., Li, D., Hao, S., Zhang, F., Zhang, X., Li, A., & Qin, X. (2022) · Rejuvenation Research · doi:10.1089/rej.2021.0081 · Cited by 36 · see citing works
Identification of exon skipping events associated with Alzheimer’s disease in the human hippocampus
Initiative, A. D. N., Han, S., Miller, J. E., Byun, S., Kim, D., Risacher, S. L., Saykin, A. J., Lee, Y., & Nho, K. T. (2019) · BMC Medical Genomics · doi:10.1186/s12920-018-0453-8 · Cited by 34 · see citing works
Fessel, J. (2019) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.09.019 · Cited by 35 · see citing works
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Yan, Y., Gao, Y., Fang, Q., Zhang, N., Kumar, G., Yan, H., Song, L., Li, J., Zhang, Y., Sun, J., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.755164 · Cited by 34 · see citing works
Temporal Gene Expression Profiles after Focal Cerebral Ischemia in Mice
Zhang, C., Zhu, Y., Wang, S., Wei, Z. Z., Jiang, M. Q., Zhang, Y., Pan, Y., Tao, S., Li, J., & Wei, L. (2018) · Aging and Disease · doi:10.14336/ad.2017.0424 · Cited by 33 · see citing works
Stefanova, N. A., Ershov, N., Maksimova, K. Y., Muraleva, N. A., Tyumentsev, M. A., & Kolosova, N. G. (2018) · The Journals of Gerontology Series A · doi:10.1093/gerona/gly198 · Cited by 32 · see citing works
Matsuno, M., Horiuchi, J., Ofusa, K., Masuda, T., & Saitoe, M. (2019) · iScience · doi:10.1016/j.isci.2019.04.014 · Cited by 31 · see citing works
Neuroprotective effects of riluzole in Alzheimer's disease: A comprehensive review
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Hypoxia-inducible factor-2α is crucial for proper brain development
Kleszka, K., Leu, T., Quinting, T., Jastrow, H., Pechlivanis, S., Fandrey, J., & Schreiber, T. (2020) · Scientific Reports · doi:10.1038/s41598-020-75838-4 · Cited by 31 · see citing works
Recent Insights on Glutamatergic Dysfunction in Alzheimer’s Disease and Therapeutic Implications
Pinky, P. D., Pfitzer, J. C., Senfeld, J. I., Hong, H., Bhattacharya, S., Suppiramaniam, V. D., Qureshi, I., & Reed, M. N. (2022) · The Neuroscientist · doi:10.1177/10738584211069897 · Cited by 27 · see citing works
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Human ankyrins and their contribution to disease biology: An update
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Exploring the selective vulnerability in Alzheimer disease using tissue specific variant analysis
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Alternative Targets to Fight Alzheimer’s Disease: Focus on Astrocytes
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Physiological and Pathological Remodeling of Cerebral Microvessels
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Can a Selective Serotonin Reuptake Inhibitor Act as a Glutamatergic Modulator?
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The effect of Riluzole on functional recovery of locomotion in the rat sciatic nerve crush model
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WNT/β-catenin Pathway: a Possible Link Between Hypertension and Alzheimer’s Disease
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Cure of Alzheimer’s Dementia Requires Addressing All of the Affected Brain Cell Types
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Riluzole and Its Prodrugs for the Treatment of Alzheimer’s Disease
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Riluzole prevents stress-induced spine plasticity in the hippocampus but mimics it in the amygdala
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Zebrafish brain RNA sequencing reveals that cell adhesion molecules are critical in brain aging
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Drug repurposing for Alzheimer’s disease: a Delphi consensus and stakeholder consultation
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Modulating Amyloid Pathology-Neural Hyperexcitability Crosstalk for Alzheimer's Disease Therapy.
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Identifying synergistic combinations of repurposed treatments for Alzheimer’s Disease
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Augmented doubly robust post-imputation inference for proteomic data
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- Authors
- Pereira, A. C., Gray, J. D., Kogan, J. F., Davidson, R. L., Rubin, T. G., Okamoto, M., Morrison, J. H., & McEwen, B. S.
- Affiliations
- Rockefeller University (US)
- University of Tsukuba (JP)
- University of California, Davis (US)
- Corresponding author
- Pereira, A C
- Gray, J D
- Venue
- Molecular Psychiatry
- Published
- 2016-03-29
- Volume
- 22
- Issue
- 2
- Pages
- 296-305
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5042881
- OpenAlex
- W2324430454
- Cited by
- 116
- References
- 90
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 5 · 2023: 11 · 2022: 17 · 2021: 19 · 2020: 14 · 2019: 12 · 2018: 9 · 2017: 8 · 2016: 2
- FWCI
- 8.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000043, P51OD011107, UL1TR001866)
- Japan Society for the Promotion of Science (16K16559)
- National Institute on Aging (K76AG054772, R37AG006647)
- National Institute of Mental Health (F32MH102065)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, riluzole, hippocampus, aging, gene expression profiling, synaptic transmission, memory, age-related cognitive decline, glutamate modulators
- MeSH terms
- Cognitive Aging, Age Factors, Aging, Alzheimer Disease, Animals, Cognition, Disease Models, Animal, Hippocampus, Male, Memory, Synaptic Transmission, Rats, Sprague-Dawley, Neuroprotective Agents, Glutamic Acid, Riluzole, Excitatory Amino Acid Transporter 2, Rats, Transcriptome
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