{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:21:14Z","timestamp":1792203674317,"version":"4.4.0"},"reference-count":113,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,8]],"date-time":"2019-12-08T00:00:00Z","timestamp":1575763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008460","name":"National Center for Complementary and Integrative Health","doi-asserted-by":"publisher","award":["R01AT008099"],"award-info":[{"award-number":["R01AT008099"]}],"id":[{"id":"10.13039\/100008460","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008460","name":"National Center for Complementary and Integrative Health","doi-asserted-by":"publisher","award":["5T32AT002688-14"],"award-info":[{"award-number":["5T32AT002688-14"]}],"id":[{"id":"10.13039\/100008460","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008460","name":"National Center for Complementary and Integrative Health","doi-asserted-by":"publisher","award":["R00AT008831"],"award-info":[{"award-number":["R00AT008831"]}],"id":[{"id":"10.13039\/100008460","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["IO1BX003440"],"award-info":[{"award-number":["IO1BX003440"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer\u2019s disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +\/   \u2212    0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW\u2019s impact on amyloid-\u03b2 plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.<\/jats:p>","DOI":"10.3390\/antiox8120630","type":"journal-article","created":{"date-parts":[[2019,12,9]],"date-time":"2019-12-09T05:54:51Z","timestamp":1575870891000},"page":"630","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8533-7045","authenticated-orcid":false,"given":"Donald G","family":"Matthews","sequence":"first","affiliation":[{"name":"Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Caruso","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles F","family":"Murchison","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"},{"name":"Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer Y","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6913-7422","authenticated-orcid":false,"given":"Kirsten M","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"},{"name":"Parkinson\u2019s Disease Research Education and Clinical Care Center, Veterans\u2019 Administration Portland Health Care System, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora E","family":"Gray","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph F","family":"Quinn","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"},{"name":"Parkinson\u2019s Disease Research Education and Clinical Care Center, Veterans\u2019 Administration Portland Health Care System, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1569-6453","authenticated-orcid":false,"given":"Amala","family":"Soumyanath","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gray, N.E., Zweig, J.A., Caruso, M., Martin, M.D., Zhu, J.Y., Quinn, J.F., and Soumyanath, A. (2018). Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice. Brain Behav.","DOI":"10.1002\/brb3.1024"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/aps.2012.3","article-title":"Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells","volume":"33","author":"Xu","year":"2012","journal-title":"Acta Pharmacol. Sin"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"347569","DOI":"10.4061\/2011\/347569","article-title":"Centella asiatica Attenuates D-Galactose-Induced Cognitive Impairment, Oxidative and Mitochondrial Dysfunction in Mice","volume":"2011","author":"Kumar","year":"2011","journal-title":"Int. J. Alzheimers Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jep.2007.11.038","article-title":"Positive modulation of cognition and mood in the healthy elderly volunteer following the administration of Centella asiatica","volume":"116","author":"Wattanathorn","year":"2008","journal-title":"J. Ethnopharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1097\/00004714-200012000-00015","article-title":"A double-blind, placebo-controlled study on the effects of Gotu Kola (Centella asiatica) on acoustic startle response in healthy subjects","volume":"20","author":"Bradwejn","year":"2000","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1211\/jpp.57.9.0018","article-title":"Centella asiatica accelerates nerve regeneration upon oral administration and contains multiple active fractions increasing neurite elongation in-vitro","volume":"57","author":"Soumyanath","year":"2005","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"262","DOI":"10.2741\/s514","article-title":"Neuroprotective role of Asiatic acid in aluminium chloride induced rat model of Alzheimer\u2019s disease","volume":"10","author":"Rather","year":"2018","journal-title":"Front. Biosci. (Schol. Ed.)"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kumar, A., Dogra, S., and Prakash, A. (2009). Neuroprotective Effects of Centella asiatica against Intracerebroventricular Colchicine-Induced Cognitive Impairment and Oxidative Stress. Int. J. Alzheimers Dis., 2009.","DOI":"10.4061\/2009\/972178"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1046\/j.1440-1681.2003.03842.x","article-title":"Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer\u2019s disease in rats","volume":"30","author":"Gupta","year":"2003","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0378-8741(01)00394-4","article-title":"Effect of different extracts of Centella asiatica on cognition and markers of oxidative stress in rats","volume":"79","author":"Gupta","year":"2002","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1007\/s10072-012-1252-1","article-title":"Mitoprotective effect of Centella asiatica against aluminum-induced neurotoxicity in rats: Possible relevance to its anti-oxidant and anti-apoptosis mechanism","volume":"34","author":"Prakash","year":"2013","journal-title":"Neurol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/ptr.2405","article-title":"Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer\u2019s disease animal model","volume":"23","author":"Dhanasekaran","year":"2009","journal-title":"Phytother. Res."},{"key":"ref_13","first-page":"381974","article-title":"Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model of Alzheimer\u2019s Disease: Investigation of a Possible Mechanism of Action","volume":"2012","author":"Soumyanath","year":"2012","journal-title":"Int. J. Alzheimers Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.brainres.2010.11.067","article-title":"Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice","volume":"1371","author":"Kurata","year":"2011","journal-title":"Brain Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.nbd.2009.06.003","article-title":"Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice","volume":"35","author":"Tong","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S18","DOI":"10.1038\/nrn1434","article-title":"Oxidative stress in neurodegeneration: Cause or consequence?","volume":"10","author":"Andersen","year":"2004","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"88","DOI":"10.4161\/cam.3.1.7402","article-title":"Oxidative stress in Alzheimer disease","volume":"3","author":"Gella","year":"2009","journal-title":"Cell Adhes. Migr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/nm0795-693","article-title":"Non-enzymatically glycated tau in Alzheimer\u2019s disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide","volume":"1","author":"Yan","year":"1995","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1097\/00001756-199209000-00012","article-title":"beta-Amyloid induces neuritic dystrophy in vitro: Similarities with Alzheimer pathology","volume":"3","author":"Pike","year":"1992","journal-title":"Neuroreport"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.neuroscience.2004.11.047","article-title":"Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer\u2019s disease","volume":"132","author":"Aucoin","year":"2005","journal-title":"Neuroscience"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1046\/j.1365-2990.2002.t01-1-00410.x","article-title":"Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer\u2019s disease and Creutzfeldt-Jakob\u2019s disease","volume":"28","author":"Ferrer","year":"2002","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1097\/NEN.0b013e31827b5713","article-title":"Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases","volume":"72","author":"Tanji","year":"2013","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1179\/135100099101534701","article-title":"Quinone reductase (NQO1), a sensitive redox indicator, is increased in Alzheimer\u2019s disease","volume":"4","author":"Raina","year":"1999","journal-title":"Redox Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3233\/JAD-132483","article-title":"The emerging role of glutathione in Alzheimer\u2019s disease","volume":"40","author":"Saharan","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.neuint.2005.12.003","article-title":"Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer\u2019s disease","volume":"48","author":"Volkel","year":"2006","journal-title":"Neurochem. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/S0304-3940(99)00751-X","article-title":"Gluthatione level is altered in lymphoblasts from patients with familial Alzheimer\u2019s disease","volume":"275","author":"Cecchi","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7023091","DOI":"10.1155\/2017\/7023091","article-title":"Centella asiatica Attenuates Mitochondrial Dysfunction and Oxidative Stress in Abeta-Exposed Hippocampal Neurons","volume":"2017","author":"Gray","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.neulet.2017.02.072","article-title":"Centella asiatica attenuates Abeta-induced neurodegenerative spine loss and dendritic simplification","volume":"646","author":"Gray","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_29","first-page":"841","article-title":"Inhibition of cPLA2 and sPLA2 activities in primary cultures of rat cortical neurons by Centella asiatica water extract","volume":"7","author":"Defillipo","year":"2012","journal-title":"Nat. Prod. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3713","DOI":"10.3390\/ijms10093713","article-title":"Antioxidant and cytotoxic activities of Centella asiatica (L) Urb","volume":"10","author":"Pittella","year":"2009","journal-title":"Int. J. Mol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"933","DOI":"10.3233\/JAD-142217","article-title":"Centella asiatica Attenuates Amyloid-beta-Induced Oxidative Stress and Mitochondrial Dysfunction","volume":"45","author":"Gray","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s11101-017-9528-y","article-title":"Centella asiatica: Phytochemistry and mechanisms of neuroprotection and cognitive enhancement","volume":"17","author":"Gray","year":"2018","journal-title":"Phytochem. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mcn.2018.09.002","article-title":"Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in beta-amyloid overexpressing mice","volume":"93","author":"Gray","year":"2018","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1097\/00005072-199709000-00002","article-title":"APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1","volume":"56","author":"Irizarry","year":"1997","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer\u2019s disease mutations: Potential factors in amyloid plaque formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1750-1326-8-2","article-title":"Neuron loss in the 5XFAD mouse model of Alzheimer\u2019s disease correlates with intraneuronal Abeta42 accumulation and Caspase-3 activation","volume":"8","author":"Eimer","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Devi, L., and Ohno, M. (2010). Phospho-eIF2alpha level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012974"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1460-9568.2005.04551.x","article-title":"Temporal memory deficits in Alzheimer\u2019s mouse models: Rescue by genetic deletion of BACE1","volume":"23","author":"Ohno","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/cne.24551","article-title":"Sex-biased hippocampal pathology in the 5XFAD mouse model of Alzheimer\u2019s disease: A multi-omic analysis","volume":"527","author":"Bundy","year":"2019","journal-title":"J. Comp. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1750-1326-10-1","article-title":"Abeta reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level","volume":"10","author":"Sadleir","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/1756-6606-3-34","article-title":"Sex- and brain region-specific acceleration of beta-amyloidogenesis following behavioral stress in a mouse model of Alzheimer\u2019s disease","volume":"3","author":"Devi","year":"2010","journal-title":"Mol. Brain"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Bhattacharya, S., Haertel, C., Maelicke, A., and Montag, D. (2014). Galantamine slows down plaque formation and behavioral decline in the 5XFAD mouse model of Alzheimer\u2019s disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089454"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.3233\/JAD-180678","article-title":"5xFAD Mice Display Sex-Dependent Inflammatory Gene Induction During the Prodromal Stage of Alzheimer\u2019s Disease","volume":"70","author":"Manji","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41598-018-37312-0","article-title":"Dissociable cognitive impairments in two strains of transgenic Alzheimer\u2019s disease mice revealed by a battery of object-based tests","volume":"9","author":"Creighton","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.neubiorev.2015.09.002","article-title":"The problem of genotype and sex differences in life expectancy in transgenic AD mice","volume":"57","author":"Rae","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jep.2016.01.013","article-title":"Centella asiatica modulates antioxidant and mitochondrial pathways and improves cognitive function in mice","volume":"180","author":"Gray","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/bmc.564","article-title":"Identification of triterpenoid compounds of Centella asiatica by thin-layer chromatography and mass spectrometry","volume":"20","author":"Bonfill","year":"2006","journal-title":"Biomed. Chromatogr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1111\/j.1750-3639.2011.00560.x","article-title":"Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer\u2019s disease","volume":"22","author":"Aso","year":"2012","journal-title":"Brain Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.nbd.2008.10.006","article-title":"Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model","volume":"33","author":"Kimura","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.trci.2017.07.002","article-title":"Gamma rhythm low field magnetic stimulation alleviates neuropathologic changes and rescues memory and cognitive impairments in a mouse model of Alzheimer\u2019s disease","volume":"3","author":"Zhen","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"48","DOI":"10.3389\/fncir.2017.00048","article-title":"Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer\u2019s Disease","volume":"11","author":"Zhen","year":"2017","journal-title":"Front. Neural Circuits"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.expneurol.2013.10.001","article-title":"Combination therapy in a transgenic model of Alzheimer\u2019s disease","volume":"250","author":"Aytan","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/j.1460-9568.2009.07031.x","article-title":"Genetic reductions of beta-site amyloid precursor protein-cleaving enzyme 1 and amyloid-beta ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer\u2019s disease model mice","volume":"31","author":"Devi","year":"2010","journal-title":"Eur. J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.bbr.2005.05.011","article-title":"Beta estrogen receptor knockout (BERKO) mice present attenuated hippocampal CA1 long-term potentiation and related memory deficits in contextual fear conditioning","volume":"164","author":"Day","year":"2005","journal-title":"Behav. Brain Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/j.physbeh.2011.12.016","article-title":"Role of gonadal hormones in anxiety and fear memory formation and inhibition in male mice","volume":"105","author":"McDermott","year":"2012","journal-title":"Physiol. Behav."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.yhbeh.2018.08.012","article-title":"Androgen receptor is a negative regulator of contextual fear memory in male mice","volume":"106","author":"Ramzan","year":"2018","journal-title":"Horm. Behav."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/npp.2016.174","article-title":"Sex Differences in Context Fear Generalization and Recruitment of Hippocampus and Amygdala during Retrieval","volume":"42","author":"Keiser","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0896-6273(00)81122-8","article-title":"Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I","volume":"24","author":"Janz","year":"1999","journal-title":"Neuron"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/24790","article-title":"Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein","volume":"396","author":"Migaud","year":"1998","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/S0006-3223(01)01229-X","article-title":"Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus","volume":"50","author":"Thome","year":"2001","journal-title":"Biol. Psychiatry"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.neuroscience.2007.06.036","article-title":"Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood","volume":"149","author":"Glantz","year":"2007","journal-title":"Neuroscience"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1002\/cne.23306","article-title":"In vivo characterization of a bigenic fluorescent mouse model of Alzheimer\u2019s disease with neurodegeneration","volume":"521","author":"Crowe","year":"2013","journal-title":"J. Comp. Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3389\/fncel.2018.00224","article-title":"Environmental Enrichment Improves Cognitive Deficits, AD Hallmarks and Epigenetic Alterations Presented in 5xFAD Mouse Model","volume":"12","author":"Izquierdo","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.brainresbull.2017.12.013","article-title":"Myelin changes at the early stage of 5XFAD mice","volume":"137","author":"Gu","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"196.e29","DOI":"10.1016\/j.neurobiolaging.2010.05.027","article-title":"Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Abeta aggregation in the 5XFAD mouse model of Alzheimer\u2019s disease","volume":"33","author":"Jawhar","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/cns.12809","article-title":"LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice","volume":"24","author":"Wu","year":"2018","journal-title":"CNS Neurosci. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.3233\/JAD-143120","article-title":"Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer\u2019s Disease","volume":"45","author":"Richard","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/S0969-9961(03)00079-2","article-title":"Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype","volume":"13","author":"Lanz","year":"2003","journal-title":"Neurobiol. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5161","DOI":"10.1073\/pnas.0600948103","article-title":"Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer\u2019s disease","volume":"103","author":"Jacobsen","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","first-page":"5148","article-title":"Protective effects of reduced dynamin-related protein 1 against amyloid beta-induced mitochondrial dysfunction and synaptic damage in Alzheimer\u2019s disease","volume":"25","author":"Manczak","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1126\/science.274.5284.99","article-title":"Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice","volume":"274","author":"Hsiao","year":"1996","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S0031-9384(02)00639-X","article-title":"Behavioral characterization of the Tg2576 transgenic model of Alzheimer\u2019s disease through 19 months","volume":"75","author":"King","year":"2002","journal-title":"Physiol. Behav."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.bbr.2018.11.022","article-title":"Cognitive decline in Tg2576 mice shows sex-specific differences and correlates with cerebral amyloid-beta","volume":"359","author":"Schmid","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"42270","DOI":"10.1038\/srep42270","article-title":"Neuronally-directed effects of RXR activation in a mouse model of Alzheimer\u2019s disease","volume":"7","author":"Mariani","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Yang, E.J., Ahn, S., Ryu, J., Choi, M.S., Choi, S., Chong, Y.H., Hyun, J.W., Chang, M.J., and Kim, H.S. (2015). Phloroglucinol Attenuates the Cognitive Deficits of the 5XFAD Mouse Model of Alzheimer\u2019s Disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135686"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s00401-011-0843-x","article-title":"Postsynaptic degeneration as revealed by PSD-95 reduction occurs after advanced Abeta and tau pathology in transgenic mouse models of Alzheimer\u2019s disease","volume":"122","author":"Shao","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_77","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_78","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_79","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s00401-016-1558-9","article-title":"Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Abeta generation in Alzheimer\u2019s disease","volume":"132","author":"Sadleir","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0014-4886(03)00252-8","article-title":"Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP\/PS1 transgenic mice","volume":"184","author":"Blanchard","year":"2003","journal-title":"Exp. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1097\/00005072-199803000-00002","article-title":"Dystrophic neurites of senile plaques are defective in proteins involved in exocytosis and neurotransmission","volume":"57","author":"Ferrer","year":"1998","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.2174\/138161210793176572","article-title":"Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer\u2019s disease","volume":"16","author":"Agostinho","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"245","DOI":"10.3233\/JAD-2009-1041","article-title":"Oxidative stress in vascular dementia and Alzheimer\u2019s disease: A common pathology","volume":"17","author":"Bennett","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.nbd.2005.01.026","article-title":"Endogenous oxidative stress in sporadic Alzheimer\u2019s disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids","volume":"19","author":"Onyango","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1006\/neur.1996.0059","article-title":"Energy metabolism, oxidative stress and neuronal degeneration in Alzheimer\u2019s disease","volume":"5","author":"Sims","year":"1996","journal-title":"Neurodegeneration"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0197-4580(03)00117-9","article-title":"Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer\u2019s disease","volume":"25","author":"SantaCruz","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S0197-4580(00)00114-7","article-title":"NAD(P)H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Aalzheimer\u2019s disease","volume":"21","author":"Wang","year":"2000","journal-title":"Neurobiol. Aging"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1097\/nen.0b013e31802d6da9","article-title":"Expression of Nrf2 in neurodegenerative diseases","volume":"66","author":"Ramsey","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3389\/fphar.2016.00400","article-title":"In vitro and In vivo Antioxidant, Anti-hyperlipidemic Properties and Chemical Characterization of Centella asiatica (L.) Extract","volume":"7","author":"Kumari","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"86","DOI":"10.4103\/0975-7406.129172","article-title":"Comparative study on anti-oxidant and anti-inflammatory activities of Caesalpinia crista and Centella asiatica leaf extracts","volume":"6","author":"Ramesh","year":"2014","journal-title":"J. Pharm. Bioallied Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1002\/jnr.22071","article-title":"Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia","volume":"87","author":"Krishnamurthy","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Welbat, J.U., Chaisawang, P., Pannangrong, W., and Wigmore, P. (2018). Neuroprotective Properties of Asiatic Acid against 5-Fluorouracil Chemotherapy in the Hippocampus in an Adult Rat Model. Nutrients, 10.","DOI":"10.3390\/nu10081053"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s12012-017-9424-0","article-title":"Asiatic Acid Ameliorates Doxorubicin-Induced Cardiac and Hepato-Renal Toxicities with Nrf2 Transcriptional Factor Activation in Rats","volume":"18","author":"Kamble","year":"2018","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.lfs.2016.05.004","article-title":"Neuroprotective effect of asiatic acid against spinal cord injury in rats","volume":"157","author":"Jiang","year":"2016","journal-title":"Life Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1111\/cns.12010","article-title":"Tacrine-6-ferulic acid, a novel multifunctional dimer against Alzheimer\u2019s disease, prevents oxidative stress-induced neuronal death through activating Nrf2\/ARE\/HO-1 pathway in HT22 cells","volume":"18","author":"Huang","year":"2012","journal-title":"CNS Neurosci. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.3389\/fpls.2016.01469","article-title":"Stimulatory Effects of Acibenzolar-S-Methyl on Chlorogenic Acids Biosynthesis in Centella asiatica Cells","volume":"7","author":"Ncube","year":"2016","journal-title":"Front. Plant Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1248\/bpb.30.935","article-title":"The anti-thrombotic active constituents from Centella asiatica","volume":"30","author":"Satake","year":"2007","journal-title":"Biol. Pharm. Bull."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.brainres.2010.05.072","article-title":"1,5-Dicaffeoylquinic acid-mediated glutathione synthesis through activation of Nrf2 protects against OGD\/reperfusion-induced oxidative stress in astrocytes","volume":"1347","author":"Cao","year":"2010","journal-title":"Brain Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.cbi.2009.07.017","article-title":"Protective mechanisms of 3-caffeoyl, 4-dihydrocaffeoyl quinic acid from Salicornia herbacea against tert-butyl hydroperoxide-induced oxidative damage","volume":"181","author":"Hwang","year":"2009","journal-title":"Chem. Biol. Interact."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3233\/JAD-130311","article-title":"Quantitative proteomic analysis of the hippocampus in the 5XFAD mouse model at early stages of Alzheimer\u2019s disease pathology","volume":"36","author":"Hong","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"6435861","DOI":"10.1155\/2018\/6435861","article-title":"Oxidant\/Antioxidant Imbalance in Alzheimer\u2019s Disease: Therapeutic and Diagnostic Prospects","volume":"2018","author":"Wojsiat","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"12516","DOI":"10.1073\/pnas.1819541116","article-title":"NRF2\/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer\u2019s models","volume":"116","author":"Bahn","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","first-page":"664","article-title":"Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice","volume":"8","author":"Sarroca","year":"2016","journal-title":"Aging (Albany NY)"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5167","DOI":"10.1523\/JNEUROSCI.0482-06.2006","article-title":"Reduction in mitochondrial superoxide dismutase modulates Alzheimer\u2019s disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice","volume":"26","author":"Esposito","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1097\/01.jnen.0000240468.12543.af","article-title":"Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model","volume":"65","author":"Dodwell","year":"2006","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1055\/a-0619-5710","article-title":"Differences in Neuritogenic Activity and Signaling Activation of Madecassoside, Asiaticoside, and Their Aglycones in Neuro-2a cells","volume":"84","author":"Nalinratana","year":"2018","journal-title":"Planta Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ejphar.2012.01.006","article-title":"Asiatic acid protects primary neurons against C2-ceramide-induced apoptosis","volume":"679","author":"Zhang","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1186\/s12974-017-1009-0","article-title":"Asiatic acid attenuates methamphetamine-induced neuroinflammation and neurotoxicity through blocking of NF-kB\/STAT3\/ERK and mitochondria-mediated apoptosis pathway","volume":"14","author":"Park","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"44557","DOI":"10.1074\/jbc.M111.279208","article-title":"SOD1 (copper\/zinc superoxide dismutase) deficiency drives amyloid beta protein oligomerization and memory loss in mouse model of Alzheimer disease","volume":"286","author":"Murakami","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.12659\/MSM.894024","article-title":"Nerve Protective Effect of Asiaticoside against Ischemia-Hypoxia in Cultured Rat Cortex Neurons","volume":"21","author":"Sun","year":"2015","journal-title":"Med. Sci. Monit."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1248\/bpb.b14-00055","article-title":"Neuroprotective effect of asiatic acid in rat model of focal embolic stroke","volume":"37","author":"Lee","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.neuroscience.2010.05.049","article-title":"Neuroprotective effect of 3,5-di-O-caffeoylquinic acid on SH-SY5Y cells and senescence-accelerated-prone mice 8 through the up-regulation of phosphoglycerate kinase-1","volume":"169","author":"Han","year":"2010","journal-title":"Neuroscience"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"359","DOI":"10.3233\/JAD-131913","article-title":"Caffeoylquinic acids in Centella asiatica protect against amyloid-beta toxicity","volume":"40","author":"Gray","year":"2014","journal-title":"J. Alzheimers Dis."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/8\/12\/630\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:40:28Z","timestamp":1760190028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/8\/12\/630"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,8]]},"references-count":113,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["antiox8120630"],"URL":"https:\/\/doi.org\/10.3390\/antiox8120630","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,8]]}}}