{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T21:55:28Z","timestamp":1775598928834,"version":"3.50.1"},"reference-count":89,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,9]],"date-time":"2023-04-09T00:00:00Z","timestamp":1680998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["CENTRO-01-0246-FEDER-000010"],"award-info":[{"award-number":["CENTRO-01-0246-FEDER-000010"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["LCF\/PR\/HP17\/52190001"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190001"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-03127"],"award-info":[{"award-number":["POCI-01-0145-FEDER-03127"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"name":"La Caixa Foundation","award":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"]}]},{"name":"La Caixa Foundation","award":["CENTRO-01-0246-FEDER-000010"],"award-info":[{"award-number":["CENTRO-01-0246-FEDER-000010"]}]},{"name":"La Caixa Foundation","award":["LCF\/PR\/HP17\/52190001"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190001"]}]},{"name":"La Caixa Foundation","award":["POCI-01-0145-FEDER-03127"],"award-info":[{"award-number":["POCI-01-0145-FEDER-03127"]}]},{"name":"La Caixa Foundation","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}]},{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["CENTRO-01-0246-FEDER-000010"],"award-info":[{"award-number":["CENTRO-01-0246-FEDER-000010"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["LCF\/PR\/HP17\/52190001"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190001"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-03127"],"award-info":[{"award-number":["POCI-01-0145-FEDER-03127"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD), which predominantly affects women, involves at its onset a metabolic deregulation associated with a synaptic failure. Here, we performed a behavioral, neurophysiological and neurochemical characterization of 9-month-old female APPswe\/PS1dE9 (APP\/PS1) mice as a model of early AD. These animals showed learning and memory deficits in the Morris water maze, increased thigmotaxis and anxiety-like behavior and showed signs of fear generalization. Long-term potentiation (LTP) was decreased in the prefrontal cortex (PFC), but not in the CA1 hippocampus or amygdala. This was associated with a decreased density of sirtuin-1 in cerebrocortical synaptosomes and a decreased density of sirtuin-1 and sestrin-2 in total cerebrocortical extracts, without alterations of sirtuin-3 levels or of synaptic markers (syntaxin, synaptophysin, SNAP25, PSD95). However, activation of sirtuin-1 did not affect or recover PFC-LTP deficit in APP\/PS1 female mice; instead, inhibition of sirtuin-1 increased PFC-LTP magnitude. It is concluded that mood and memory dysfunction in 9-month-old female APP\/PS1 mice is associated with a parallel decrease in synaptic plasticity and in synaptic sirtuin-1 levels in the prefrontal cortex, although sirtiun1 activation failed to restore abnormal cortical plasticity.<\/jats:p>","DOI":"10.3390\/ijms24086968","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T03:49:29Z","timestamp":1681098569000},"page":"6968","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Downregulation of Sirtuin 1 Does Not Account for the Impaired Long-Term Potentiation in the Prefrontal Cortex of Female APPswe\/PS1dE9 Mice Modelling Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"given":"C\u00e1tia R.","family":"Lopes","sequence":"first","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Joana S.","family":"Silva","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Joana","family":"Santos","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9616-8400","authenticated-orcid":false,"given":"Matilde S.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Daniela","family":"Madeira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Andreia","family":"Oliveira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Ana","family":"Moreira-de-S\u00e1","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-4644","authenticated-orcid":false,"given":"Vanessa S.","family":"Louren\u00e7o","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Francisco Q.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7234-3411","authenticated-orcid":false,"given":"Henrique B.","family":"Silva","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Ana Patr\u00edcia","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Anabela P.","family":"Rolo","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3004-531 Coimbra, Portugal"}]},{"given":"Paula M.","family":"Canas","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8671-989X","authenticated-orcid":false,"given":"\u00c2ngelo R.","family":"Tom\u00e9","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3004-531 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2639-7697","authenticated-orcid":false,"given":"Carlos M.","family":"Palmeira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3004-531 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5122-1802","authenticated-orcid":false,"given":"Jo\u00e3o Pedro","family":"Lopes","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Rodrigo A.","family":"Cunha","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Paula","family":"Agostinho","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7486-5056","authenticated-orcid":false,"given":"Samira G.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s00401-018-1920-1","article-title":"Sex differences in Alzheimer\u2019s disease and common neuropathologies of aging","volume":"136","author":"Oveisgharan","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_2","first-page":"a006189","article-title":"Neuropathological alterations in Alzheimer disease","volume":"1","author":"Frosch","year":"2011","journal-title":"Cold Spring Harbor Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Morales, V., Gonz\u00e1lez-Acedo, A., Melguizo-Rodr\u00edguez, L., Pardo-Moreno, T., Costela-Ruiz, V.J., Montiel-Troya, M., and Ramos-Rodr\u00edguez, J.J. (2021). Current understanding of the physiopathology, diagnosis and therapeutic approach to Alzheimer\u2019s disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121910"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1111\/j.1471-4159.2006.03935.x","article-title":"Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer\u2019s disease","volume":"98","author":"Kirvell","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neuropharm.2013.08.026","article-title":"Predominant loss of glutamatergic terminal markers in a \u03b2-amyloid peptide model of Alzheimer\u2019s disease","volume":"76","author":"Canas","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101208","DOI":"10.1016\/j.arr.2020.101208","article-title":"Synaptic basis of Alzheimer\u2019s disease: Focus on synaptic amyloid beta, P-tau and mitochondria","volume":"65","author":"John","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.3233\/JAD-171125","article-title":"18F-FDG PET for prediction of conversion to Alzheimer\u2019s disease dementia in people with mild cognitive impairment: An updated systematic review of test accuracy","volume":"64","author":"Smailagic","year":"2018","journal-title":"J. Alzheimer Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1152\/physrev.00022.2011","article-title":"Sirtuin 1 and sirtuin 3: Physiological modulators of metabolism","volume":"92","author":"Nogueiras","year":"2012","journal-title":"Physiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/nature09271","article-title":"A novel pathway regulates memory and plasticity via SIRT1 and miR-134","volume":"466","author":"Gao","year":"2010","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9695","DOI":"10.1523\/JNEUROSCI.0027-10.2010","article-title":"SIRT1 is essential for normal cognitive function and synaptic plasticity","volume":"30","author":"Li","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"105152","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.105152","article-title":"Localization and expression of sirtuins 1, 2, 6 and plasticity-related proteins in the recovery period after a photothrombotic stroke in mice","volume":"29","author":"Demyanenko","year":"2020","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1007\/s11064-020-03216-7","article-title":"Ex vivo investigation of bexarotene and nicotinamide function as a protect\u0131ve agent on rat synaptosomes treated with A\u03b21-42","volume":"46","author":"Hacioglu","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"172847","DOI":"10.1016\/j.ejphar.2019.172847","article-title":"Review of the anti-inflammatory effect of SIRT1 and SIRT2 modulators on neurodegenerative diseases","volume":"867","author":"Zhang","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"908689","DOI":"10.3389\/fphys.2022.908689","article-title":"Sirtuins and cognition: Implications for learning and memory in neurological disorders","volume":"13","author":"Fagerli","year":"2022","journal-title":"Front. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.neurobiolaging.2015.10.031","article-title":"Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium","volume":"38","author":"Hohman","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1007\/s10072-020-04704-y","article-title":"Positive association of a Sirt1 variant and parameters of oxidative stress on Alzheimer\u2019s disease","volume":"42","author":"Camporez","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s12017-014-8288-8","article-title":"Distinct patterns of sirtuin expression during progression of Alzheimer\u2019s disease","volume":"16","author":"Lutz","year":"2014","journal-title":"Neuromol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e923547","DOI":"10.12659\/MSM.923547","article-title":"Sirtuin 3 mRNA expression is downregulated in the brain tissues of Alzheimer\u2019s disease patients: A bioinformatic and data mining approach","volume":"26","author":"Song","year":"2020","journal-title":"Med. Sci. Monit."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1007\/s11064-015-1630-1","article-title":"Mitochondrial Sirt3 expression is decreased in APP\/PS1 double transgenic mouse model of Alzheimer\u2019s disease","volume":"40","author":"Yang","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5011","DOI":"10.1007\/s12035-020-02079-x","article-title":"AMPK ameliorates tau acetylation and memory impairment through Sirt1","volume":"57","author":"Wang","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3169","DOI":"10.1038\/sj.emboj.7601758","article-title":"SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer\u2019s disease and amyotrophic lateral sclerosis","volume":"26","author":"Kim","year":"2007","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5604","DOI":"10.1007\/s12035-016-0087-9","article-title":"SIRT1 overexpression in mouse hippocampus induces cognitive enhancement through proteostatic and neurotrophic mechanisms","volume":"54","author":"Corpas","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1038\/s41467-019-09897-1","article-title":"SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice","volume":"10","author":"Liu","year":"2019","journal-title":"Nat. Comm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1097\/NEN.0b013e3181922348","article-title":"Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease","volume":"68","author":"Julien","year":"2009","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.bbr.2014.04.055","article-title":"Neophobia, NQO1 and SIRT1 as premorbid and prodromal indicators of AD in 3xTg-AD mice","volume":"271","author":"Peinado","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S0896-6273(00)80974-5","article-title":"Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins","volume":"19","author":"Borchelt","year":"1997","journal-title":"Neuron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/ana.20101","article-title":"Progressive age-related development of Alzheimer-like pathology in APP\/PS1 mice","volume":"55","author":"Trinchese","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/npp.2009.197","article-title":"Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer\u2019s disease","volume":"35","author":"Kilgore","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11915","DOI":"10.1038\/ncomms11915","article-title":"Early synaptic deficits in the APP\/PS1 mouse model of Alzheimer\u2019s disease involve neuronal adenosine A2A receptors","volume":"7","author":"Haberl","year":"2016","journal-title":"Nat. Comm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/0091-3057(88)90413-3","article-title":"Thigmotaxis as a test for anxiolytic activity in rats","volume":"31","author":"Treit","year":"1988","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3389\/fnins.2013.00063","article-title":"An old test for new neurons: Refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis","volume":"7","author":"Garthe","year":"2013","journal-title":"Front. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1146\/annurev.neuro.23.1.155","article-title":"Emotion circuits in the brain","volume":"23","author":"LeDoux","year":"2000","journal-title":"Ann. Rev. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S0028-3908(98)00023-9","article-title":"Synapses in hippocampus occupy only 1\u20132% of cell membranes and are spaced less than half-micron apart: A quantitative ultrastructural analysis with discussion of physiological implications","volume":"37","author":"Rusakov","year":"1998","journal-title":"Neuropharmacology"},{"key":"ref_34","first-page":"679","article-title":"Slowing ageing by design: The rise of NAD+ and sirtuin-activating compounds. Nature reviews","volume":"17","author":"Bonkowski","year":"2016","journal-title":"Mol. Cell. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2772","DOI":"10.1073\/pnas.1303628110","article-title":"Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism","volume":"110","author":"Gertz","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1016\/j.neurobiolaging.2015.05.010","article-title":"Behavioral abnormalities in APPSwe\/PS1dE9 mouse model of AD-like pathology: Comparative analysis across multiple behavioral domains","volume":"36","author":"Janus","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8936","DOI":"10.1007\/s12035-018-1030-z","article-title":"Adenosine augmentation evoked by an ENT1 inhibitor improves memory impairment and neuronal plasticity in the APP\/PS1 mouse model of Alzheimer\u2019s disease","volume":"55","author":"Lee","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s12974-019-1450-3","article-title":"Urolithin A attenuates memory impairment and neuroinflammation in APP\/PS1 mice","volume":"16","author":"Gong","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"170","DOI":"10.3389\/fncel.2020.00170","article-title":"Metformin ameliorates synaptic defects in a mouse model of AD by inhibiting Cdk5 activity","volume":"14","author":"Wang","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/path.2565","article-title":"Morphological alterations to neurons of the amygdala and impaired fear conditioning in a transgenic mouse model of Alzheimer\u2019s disease","volume":"219","author":"Knafo","year":"2009","journal-title":"J. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1523\/JNEUROSCI.2127-17.2017","article-title":"A\u03b2 mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer\u2019s disease","volume":"38","author":"Kommaddi","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.bbr.2011.03.041","article-title":"A detailed analysis of the early context extinction deficits seen in APPswe\/PS1dE9 female mice and their relevance to preclinical Alzheimer\u2019s disease","volume":"222","author":"Bonardi","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.neurobiolaging.2021.12.009","article-title":"Both male and female APPswe\/PSEN1dE9 mice are impaired in spatial memory and cognitive flexibility at 9 months of age","volume":"113","author":"Hulshof","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.bbr.2013.11.046","article-title":"Novel behavioural characteristics of female APPSwe\/PS1\u0394E9 double transgenic mice","volume":"260","author":"Cheng","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.biopsych.2015.04.010","article-title":"Fear generalization and anxiety: Behavioral and neural mechanisms","volume":"78","author":"Dunsmoor","year":"2015","journal-title":"Biol. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.jad.2015.09.069","article-title":"The prevalence of neuropsychiatric symptoms in Alzheimer\u2019s disease: Systematic review and meta-analysis","volume":"190","author":"Zhao","year":"2016","journal-title":"J. Affect. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1093\/brain\/awn082","article-title":"Fear conditioning in frontotemporal lobar degeneration and Alzheimer\u2019s disease","volume":"131","author":"Hoefer","year":"2008","journal-title":"Brain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.neurobiolaging.2019.11.003","article-title":"Fear acquisition and extinction deficits in amnestic mild cognitive impairment and early Alzheimer\u2019s disease","volume":"87","author":"Nasrouei","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nrn3677","article-title":"Hippocampal synaptic plasticity, spatial memory and anxiety","volume":"15","author":"Bannerman","year":"2014","journal-title":"Nat. Neurosci. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/j.neurobiolaging.2008.08.005","article-title":"Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe\/PS1\u03b4E9-deleted transgenic mice model of \u00df-amyloidosis","volume":"31","author":"Volianskis","year":"2010","journal-title":"Neurobiol. Aging"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"772980","DOI":"10.3389\/fnagi.2021.772980","article-title":"Deficits in N-methyl-D-aspartate receptor function and synaptic plasticity in hippocampal CA1 in APP\/PS1 mouse model of Alzheimer\u2019s disease","volume":"13","author":"Xu","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature14396","article-title":"A prefrontal-thalamo-hippocampal circuit for goal-directed spatial navigation","volume":"522","author":"Ito","year":"2015","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7123","DOI":"10.1073\/pnas.1720117115","article-title":"Coordinated prefrontal-hippocampal activity and navigation strategy-related prefrontal firing during spatial memory formation","volume":"115","author":"Espinosa","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.arr.2012.11.001","article-title":"Association between prefrontal activity and volume change in prefrontal and medial temporal lobes in aging and dementia: A review","volume":"12","author":"Maillet","year":"2013","journal-title":"Ageing Res. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.brs.2020.05.013","article-title":"LTP-like cortical plasticity predicts conversion to dementia in patients with memory impairment","volume":"13","author":"Motta","year":"2020","journal-title":"Brain Stimul."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/j.biopsych.2007.02.027","article-title":"Cortical plasticity in Alzheimer\u2019s disease in humans and rodents","volume":"62","author":"Battaglia","year":"2007","journal-title":"Biol. Psychiatry"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1093\/brain\/awy354","article-title":"Inhibition of EHMT1\/2 rescues synaptic and cognitive functions for Alzheimer\u2019s disease","volume":"142","author":"Zheng","year":"2019","journal-title":"Brain"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Mu, L., Cai, J., Gu, B., Yu, L., Li, C., Liu, Q.S., and Zhao, L. (2022). Treadmill exercise prevents decline in spatial learning and memory in 3\u00d7Tg-AD mice through enhancement of structural synaptic plasticity of the hippocampus and prefrontal cortex. Cells, 11.","DOI":"10.3390\/cells11020244"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.neurobiolaging.2022.06.005","article-title":"APOE4 homozygote females are resistant to the beneficial effects of 17\u03b2-estradiol on memory and CA1 dendritic spine density in the EFAD mouse model of Alzheimer\u2019s disease","volume":"118","author":"Taxier","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1016\/j.neurobiolaging.2008.01.003","article-title":"Modification upon aging of the density of presynaptic modulation systems in the hippocampus","volume":"30","author":"Canas","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7833","DOI":"10.1073\/pnas.1423088112","article-title":"Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress","volume":"112","author":"Kaster","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"105137","DOI":"10.1016\/j.nbd.2020.105137","article-title":"Adenosine A2A receptors format long-term depression and memory strategies in a mouse model of Angelman syndrome","volume":"146","author":"Lopes","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/ana.410270502","article-title":"Synapse loss in frontal cortex biopsies in Alzheimer\u2019s disease: Correlation with cognitive severity","volume":"27","author":"DeKosky","year":"1990","journal-title":"Ann. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/j.neurobiolaging.2007.04.010","article-title":"Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease","volume":"29","author":"Kashani","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/s41598-018-19154-y","article-title":"Moderate decline in select synaptic markers in the prefrontal cortex (BA9) of patients with Alzheimer\u2019s disease at various cognitive stages","volume":"8","author":"Poirel","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/j.neurobiolaging.2005.09.012","article-title":"Hippocampal synaptic loss in early Alzheimer\u2019s disease and mild cognitive impairment","volume":"27","author":"Scheff","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.jalz.2015.12.005","article-title":"Meta-analysis of synaptic pathology in Alzheimer\u2019s disease reveals selective molecular vesicular machinery vulnerability","volume":"12","author":"Overk","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1093\/brain\/awv127","article-title":"First effects of rising amyloid-\u03b2 in transgenic mouse brain: Synaptic transmission and gene expression","volume":"138","author":"Cummings","year":"2015","journal-title":"Brain"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e12791","DOI":"10.1111\/acel.12791","article-title":"Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer\u2019s disease","volume":"17","author":"Prieto","year":"2018","journal-title":"Aging Cell."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/s41419-021-04237-y","article-title":"Hippocampal disruptions of synaptic and astrocyte metabolism are primary events of early amyloid pathology in the 5xFAD mouse model of Alzheimer\u2019s disease","volume":"12","author":"Andersen","year":"2021","journal-title":"Cell. Death Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.5213\/inj.1938036.018","article-title":"Dysfunctional mitochondrial bioenergetics and synaptic degeneration in Alzheimer disease","volume":"23","author":"Tang","year":"2019","journal-title":"Int. Neurourol. J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"690168","DOI":"10.3389\/fnana.2021.690168","article-title":"Selective regional loss of cortical synapses lacking presynaptic mitochondria in the 5xFAD mouse model","volume":"15","author":"Seo","year":"2021","journal-title":"Front. Neuroanat."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Kumar, R., Chaterjee, P., Sharma, P.K., Singh, A.K., Gupta, A., Gill, K., Tripathi, M., Dey, A.B., and Dey, S. (2013). Sirtuin1: A promising serum protein marker for early detection of Alzheimer\u2019s disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061560"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Weir, H.J., Murray, T.K., Kehoe, P.G., Love, S., Verdin, E.M., O\u2019Neill, M.J., Lane, J.D., and Balthasar, N. (2012). CNS SIRT3 expression is altered by reactive oxygen species and in Alzheimer\u2019s disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048225"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e12679","DOI":"10.1111\/acel.12679","article-title":"SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"17","author":"Lee","year":"2018","journal-title":"Aging Cell."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Chen, S.D., Yang, J.L., Lin, T.K., and Yang, D.I. (2019). Emerging roles of sestrins in neurodegenerative diseases: Counteracting oxidative stress and beyond. J. Clin. Med., 8.","DOI":"10.3390\/jcm8071001"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.expneurol.2013.12.009","article-title":"Induction of sestrin2 as an endogenous protective mechanism against amyloid beta-peptide neurotoxicity in primary cortical culture","volume":"253","author":"Chen","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.3233\/JAD-160479","article-title":"Relative alterations in blood-based levels of sestrin in Alzheimer\u2019s disease and mild cognitive impairment patients","volume":"54","author":"Rai","year":"2016","journal-title":"J. Alzheimer Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1038\/s41380-019-0352-1","article-title":"SIRT1 in forebrain excitatory neurons produces sexually dimorphic effects on depression-related behaviors and modulates neuronal excitability and synaptic transmission in the medial prefrontal cortex","volume":"25","author":"Lei","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13293-023-00487-x","article-title":"Sex-divergent effects on the NAD+-dependent deacetylase sirtuin signaling across the olfactory-entorhinal-amygdaloid axis in Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"14","author":"Ferrer","year":"2023","journal-title":"Biol. Sex. Diff."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1523\/JNEUROSCI.1259-22.2023","article-title":"Neuronal SIRT3 deletion predisposes to female-specific alterations in cellular metabolism, memory, and network excitability","volume":"43","author":"Fulton","year":"2023","journal-title":"J. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1038\/npp.2016.98","article-title":"Adenosine A2A receptors in the amygdala control synaptic plasticity and contextual fear memory","volume":"41","author":"Machado","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1111\/ejn.12851","article-title":"Adenosine A2b receptors control A1 receptor-mediated inhibition of synaptic transmission in the mouse hippocampus","volume":"41","author":"Pires","year":"2015","journal-title":"Eur. J. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Lopes, C.R., Oliveira, A., Gaspar, I., Rodrigues, M.S., Santos, J., Szab\u00f3, E., Silva, H.B., Tom\u00e9, \u00c2.R., Canas, P.M., and Agostinho, P. (2023). Effects of chronic caffeine consumption on synaptic function, metabolism and adenosine modulation in different brain areas. Biomolecules, 13.","DOI":"10.3390\/biom13010106"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jneumeth.2006.12.018","article-title":"Capabilities of the WinLTP data acquisition program extending beyond basic LTP experimental functions","volume":"162","author":"Anderson","year":"2007","journal-title":"J. Neurosci. Meth."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"14741","DOI":"10.1523\/JNEUROSCI.3728-09.2009","article-title":"Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway","volume":"29","author":"Canas","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1111\/j.1471-4159.1992.tb09420.x","article-title":"Ecto-5\u2019-nucleotidase is associated with cholinergic nerve terminals in the hippocampus but not in the cerebral cortex of the rat","volume":"59","author":"Cunha","year":"1992","journal-title":"J. Neurochem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0006-8993(03)03247-5","article-title":"Subcellular localization of adenosine A1 receptors in nerve terminals and synapses of the rat hippocampus","volume":"987","author":"Rebola","year":"2003","journal-title":"Brain Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ab.2012.01.012","article-title":"Glyceraldehyde-3-phosphate dehydrogenase: A universal internal control for Western blots in prokaryotic and eukaryotic cells","volume":"423","author":"Wu","year":"2012","journal-title":"Anal. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/6968\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:12:51Z","timestamp":1760123571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/6968"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,9]]},"references-count":89,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24086968"],"URL":"https:\/\/doi.org\/10.3390\/ijms24086968","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,9]]}}}