{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:23:33Z","timestamp":1787203413311,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"crossref","award":["2022B7AFK2"],"award-info":[{"award-number":["2022B7AFK2"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2022B7AFK2"],"award-info":[{"award-number":["2022B7AFK2"]}],"id":[{"id":"https:\/\/ror.org\/0341vw408","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Synaptic dysfunction is a major contributor to cognitive decline in Alzheimer\u2019s disease (AD) and represents an attractive therapeutic target. Here, we investigated whether chronic isoserine treatment improves cognition and alters the expression of synaptic-related genes in APP\/PS1 mice. Isoserine was well tolerated and did not adversely affect body weight. In the Morris water maze, isoserine improved probe-trial performance in APP\/PS1 mice, significantly reducing latency to the first platform-location crossing, while time spent in the target quadrant showed a directionally consistent but non-significant increase. To identify molecular correlates, we profiled 84 synaptic-related genes using a targeted RT2 Profiler PCR Array. Gene-level factorial analyses identified several nominal treatment-associated effects, but no individual isoserine effect in APP\/PS1 mice remained significant after false-discovery-rate correction. In contrast, module-level analyses identified False-discovery rate (FDR)-significant changes in NF-\u03baB\/inflammatory, synaptic-maintenance, and glutamatergic-signaling gene-expression modules, with significant genotype \u00d7 treatment interactions for the NF-\u03baB\/inflammatory and synaptic-maintenance modules. Exploratory heatmap and principal component analyses further illustrated disease-context-dependent expression patterns. Western blot analyses showed that isoserine reduced nuclear factor kappa B (NF-\u03baB p65) and NMDA receptor subunit GluN2B (GluN2B) and increased postsynaptic density protein 95 (PSD-95) levels in APP\/PS1 mice. These findings suggest that isoserine improves spatial memory retention and coordinately remodels synaptic and inflammatory molecular programs in APP\/PS1 mice.<\/jats:p>","DOI":"10.3390\/cells15161487","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:12:11Z","timestamp":1787069531000},"page":"1487","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Isoserine Improves Spatial Memory and Remodels Synaptic and Inflammatory Gene-Expression Programs in APP\/PS1 Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Alessandra","family":"Saitta","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"},{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Basilotta","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Lanza","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5282-1690","authenticated-orcid":false,"given":"Michele","family":"Scuruchi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Casili","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Giovani","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3730-2590","authenticated-orcid":false,"given":"Agata","family":"Copani","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2663-6387","authenticated-orcid":false,"given":"Emanuela","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7304-7430","authenticated-orcid":false,"given":"Salvatore","family":"Oddo","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Caccamo","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Stru\u017cy\u0144ska, L., Adamiak, K., and Sidoryk-W\u0119grzynowicz, M. (2026). Tau and \u03b2-amyloid relevant pathology as a central therapeutic target in Alzheimer\u2019s disease. Biomolecules, 16.","DOI":"10.3390\/biom16040595"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0197-4580(90)90059-9","article-title":"Quantitative assessment of cortical synaptic density in Alzheimer\u2019s disease","volume":"11","author":"Scheff","year":"1990","journal-title":"Neurobiol. Aging"},{"key":"ref_3","first-page":"572","article-title":"Physical basis of cognitive alterations in Alzheimer\u2019s disease: Synapse loss is the major correlate of cognitive impairment","volume":"30","author":"Terry","year":"1991","journal-title":"Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1212\/01.wnl.0000260698.46517.8f","article-title":"Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment","volume":"68","author":"Scheff","year":"2007","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.molmed.2005.02.009","article-title":"Alzheimer\u2019s disease: A\u03b2, tau and synaptic dysfunction","volume":"11","author":"LaFerla","year":"2005","journal-title":"Trends Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/416535a","article-title":"Naturally secreted oligomers of amyloid \u03b2 protein potently inhibit hippocampal long-term potentiation in vivo","volume":"416","author":"Walsh","year":"2002","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/nm1782","article-title":"Amyloid-\u03b2 protein dimers isolated directly from Alzheimer\u2019s brains impair synaptic plasticity and memory","volume":"14","author":"Shankar","year":"2008","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1074069","article-title":"Alzheimer\u2019s disease is a synaptic failure","volume":"298","author":"Selkoe","year":"2002","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/nn.2583","article-title":"Amyloid-\u03b2\u2013induced neuronal dysfunction in Alzheimer\u2019s disease: From synapses toward neural networks","volume":"13","author":"Palop","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"De Plano, L.M., Saitta, A., Oddo, S., and Caccamo, A. (2024). Navigating Alzheimer\u2019s disease mouse models: Age-related pathology and cognitive deficits. Biomolecules, 14.","DOI":"10.3390\/biom14111405"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.neurobiolaging.2003.09.008","article-title":"APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1","volume":"25","author":"Jankowsky","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.nbd.2004.10.022","article-title":"Episodic-like memory deficits in the APPswe\/PS1dE9 mouse model of Alzheimer\u2019s disease: Relationships to \u03b2-amyloid deposition and neurotransmitter abnormalities","volume":"18","author":"Savonenko","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5089","DOI":"10.1523\/JNEUROSCI.21-14-05089.2001","article-title":"Experience-dependent gene expression in the rat hippocampus after spatial learning: A comparison of the immediate-early genesArc, c-fos, and zif268","volume":"21","author":"Guzowski","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nn.2708","article-title":"New views of Arc, a master regulator of synaptic plasticity","volume":"14","author":"Shepherd","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Minatohara, K., Akiyoshi, M., and Okuno, H. (2016). Role of immediate-early genes in synaptic plasticity and neuronal ensembles underlying the memory trace. Front. Mol. Neurosci., 8.","DOI":"10.3389\/fnmol.2015.00078"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"22687","DOI":"10.1073\/pnas.1012851108","article-title":"CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer\u2019s disease","volume":"107","author":"Caccamo","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrn1517","article-title":"PDZ domain proteins of synapses","volume":"5","author":"Kim","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e23798","DOI":"10.7554\/eLife.23798","article-title":"NPTX2 and cognitive dysfunction in Alzheimer\u2019s Disease","volume":"6","author":"Xiao","year":"2017","journal-title":"eLife"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/sj.cdd.4401837","article-title":"Roles for NF-\u03baB in nerve cell survival, plasticity, and disease","volume":"13","author":"Mattson","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1177\/0271678X17744123","article-title":"GAT3 selective substrate l-isoserine upregulates GAT3 expression and increases functional recovery after a focal ischemic stroke in mice","volume":"39","author":"Lie","year":"2019","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/nprot.2006.116","article-title":"Morris water maze: Procedures for assessing spatial and related forms of learning and memory","volume":"1","author":"Vorhees","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1093\/ilar\/ilu013","article-title":"Assessing spatial learning and memory in rodents","volume":"55","author":"Vorhees","year":"2014","journal-title":"ILAR J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.neuron.2014.05.004","article-title":"The intersection of amyloid beta and tau at synapses in Alzheimer\u2019s disease","volume":"82","author":"Hyman","year":"2014","journal-title":"Neuron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.tins.2017.04.002","article-title":"Synaptic impairment in Alzheimer\u2019s disease: A dysregulated symphony","volume":"40","author":"Forner","year":"2017","journal-title":"Trends Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Meftah, S., and Gan, J. (2023). Alzheimer\u2019s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression. Front. Synaptic Neurosci., 15.","DOI":"10.3389\/fnsyn.2023.1129036"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gallo, F.T., Katche, C., Morici, J.F., Medina, J.H., and Weisstaub, N.V. (2018). Immediate early genes, memory and psychiatric disorders: Focus on c-Fos, Egr1 and Arc. Front. Behav. Neurosci., 12.","DOI":"10.3389\/fnbeh.2018.00079"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Dresselhaus, E.C., and Meffert, M.K. (2019). Cellular specificity of NF-\u03baB function in the nervous system. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01043"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kaltschmidt, B., Helweg, L.P., Greiner, J.F., and Kaltschmidt, C. (2022). NF-\u03baB in neurodegenerative diseases: Recent evidence from human genetics. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.954541"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"E6983","DOI":"10.1073\/pnas.1517045112","article-title":"PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density","volume":"112","author":"Chen","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"109194","DOI":"10.1016\/j.celrep.2021.109194","article-title":"PSD-95 protects synapses from \u03b2-amyloid","volume":"35","author":"Dore","year":"2021","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13195-022-01002-x","article-title":"Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer\u2019s disease","volume":"14","author":"Carlyle","year":"2022","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1002\/alz.12353","article-title":"Longitudinal CSF proteomics identifies NPTX2 as a prognostic biomarker of Alzheimer\u2019s disease","volume":"17","author":"Libiger","year":"2021","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1186\/s13195-025-01893-6","article-title":"Cerebrospinal fluid NPTX2 and [18F]FDG PET track serotonergic vulnerability to neurodegeneration in prodromal Alzheimer\u2019s disease","volume":"17","author":"Massa","year":"2025","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1038\/s41591-025-03565-2","article-title":"A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer\u2019s disease","volume":"31","author":"Oh","year":"2025","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"877","DOI":"10.3233\/JAD-220747","article-title":"NMDA receptor GluN2B subunit is involved in excitotoxicity mediated by death-associated protein kinase 1 in Alzheimer\u2019s disease","volume":"91","author":"Xu","year":"2023","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"S\u00fcdkamp, N., Shchyglo, O., and Manahan-Vaughan, D. (2024). GluN2A or GluN2B subunits of the NMDA receptor contribute to changes in neuronal excitability and impairments in LTP in the hippocampus of aging mice but do not mediate detrimental effects of oligomeric A\u03b2 (1\u201342). Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1377085"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13195-020-00588-4","article-title":"The clinical promise of biomarkers of synapse damage or loss in Alzheimer\u2019s disease","volume":"12","author":"Zetterberg","year":"2020","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Subramanian, J., Savage, J.C., and Tremblay, M.-\u00c8. (2020). Synaptic loss in Alzheimer\u2019s disease: Mechanistic insights provided by two-photon in vivo imaging of transgenic mouse models. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.592607"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lanza, M., Scuruchi, M., Saitta, A., Basilotta, R., Aliquo, F., Casili, G., Esposito, E., Copani, A., Oddo, S., and Caccamo, A. (2026). Aberrant Cell Cycle Gene Expression in a Transgenic Mouse Model of Alzheimer\u2019s Disease. Cells, 15.","DOI":"10.3390\/cells15020132"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Casili, G., Ardizzone, A., Basilotta, R., Lanza, M., Filippone, A., Paterniti, I., Esposito, E., and Campolo, M. (2021). The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia-Reperfusion. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111886"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/16\/1487\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:27:21Z","timestamp":1787200041000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/16\/1487"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":40,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cells15161487"],"URL":"https:\/\/doi.org\/10.3390\/cells15161487","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]}}}