{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T21:39:15Z","timestamp":1775943555599,"version":"3.50.1"},"reference-count":84,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T00:00:00Z","timestamp":1606867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive degenerative disorder and the most common cause of dementia in aging populations. Although the pathological hallmarks of AD are well defined, currently no effective therapy exists. Liver growth factor (LGF) is a hepatic albumin\u2013bilirubin complex with activity as a tissue regenerating factor in several neurodegenerative disorders such as Parkinson\u2019s disease and Friedreich\u2019s ataxia. Our aim here was to analyze the potential therapeutic effect of LGF on the APPswe mouse model of AD. Twenty-month-old mice received intraperitoneal (i.p.) injections of 1.6 \u00b5g LGF or saline, twice a week during three weeks. Mice were sacrificed one week later, and the hippocampus and dorsal cortex were prepared for immunohistochemical and biochemical studies. LGF treatment reduced amyloid-\u03b2 (A\u03b2) content, phospho-Tau\/Tau ratio and the number of A\u03b2 plaques with diameter larger than 25 \u00b5m. LGF administration also modulated protein ubiquitination and HSP70 protein levels, reduced glial reactivity and inflammation, and the expression of the pro-apoptotic protein Bax. Because the administration of this factor also restored cognitive damage in APPswe mice, we propose LGF as a novel therapeutic tool that may be useful for the treatment of AD.<\/jats:p>","DOI":"10.3390\/ijms21239201","type":"journal-article","created":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T20:25:49Z","timestamp":1606940749000},"page":"9201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Liver Growth Factor \u201cLGF\u201d as a Therapeutic Agent for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6357-105X","authenticated-orcid":false,"given":"Rafael","family":"Gonzalo-Gobernado","sequence":"first","affiliation":[{"name":"Servicio de Neurobiolog\u00eda, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"},{"name":"National Centre for Biotechnology (CNB), CSIC, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Perucho","sequence":"additional","affiliation":[{"name":"Servicio de Neurobiolog\u00eda, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Vallejo-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Servicio de Neurobiolog\u00eda, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Jos\u00e9","family":"Casarejos","sequence":"additional","affiliation":[{"name":"Servicio de Neurobiolog\u00eda, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Reimers","sequence":"additional","affiliation":[{"name":"Servicio de Neurobiolog\u00eda, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriano","family":"Jim\u00e9nez-Escrig","sequence":"additional","affiliation":[{"name":"Servicio de Neurobiolog\u00eda, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"},{"name":"Servicio de Neurolog\u00eda, Hospital Ram\u00f3n y Cajal, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Servicio de Neurobiolog\u00eda, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonzalo M.","family":"Ulzurrun de Asanza","sequence":"additional","affiliation":[{"name":"Servicio de Neurobiolog\u00eda, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0126-250X","authenticated-orcid":false,"given":"Eulalia","family":"Baz\u00e1n","sequence":"additional","affiliation":[{"name":"Servicio de Neurobiolog\u00eda, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Stephens, K., and Amemiya, A. Alzheimer Disease Overview. GeneReviews\u00ae, University of Washington, Seattle."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/978-94-007-5416-4_14","article-title":"Alzheimer\u2019s disease","volume":"65","author":"Radanovic","year":"2012","journal-title":"Subcell. Biochem."},{"key":"ref_3","first-page":"a006189","article-title":"Neuropathological alterations in Alzheimer disease","volume":"1","author":"Frosch","year":"2011","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1146\/annurev-med-092611-084441","article-title":"Toward the treatment and prevention of Alzheimer\u2019s disease: Rational strategies and recent progress","volume":"64","author":"Gandy","year":"2013","journal-title":"Annu. Rev. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1042\/bj2350049","article-title":"Purification of a liver DNA-synthesis promoter from plasma of partially hepatectomized rats","volume":"235","author":"Escartin","year":"1986","journal-title":"Biochem. J."},{"key":"ref_6","first-page":"173","article-title":"Liver growth factor as a tissue regenerating factor in neurodegenerative diseases","volume":"9","author":"Perucho","year":"2014","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1369\/jhc.2009.952275","article-title":"Mobilization of neural stem cells and generation of new neurons in 6-OHDA-lesioned rats by intracerebroventricular infusion of liver growth factor","volume":"57","author":"Reimers","year":"2009","journal-title":"J. Histochem. Cytochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1369\/jhc.5A6805.2005","article-title":"Intrastriatal infusion of liver growth factor stimulates dopamine terminal sprouting and partially restores motor function in 6-hydroxydopamine-lesioned rats","volume":"54","author":"Reimers","year":"2006","journal-title":"J. Histochem. Cytochem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gonzalo-Gobernado, R., Calatrava-Ferreras, L., Reimers, D., Herranz, A.S., Rodriguez-Serrano, M., Miranda, C., Jimenez-Escrig, A., Diaz-Gil, J.J., and Bazan, E. (2013). Neuroprotective activity of peripherally administered liver growth factor in a rat model of Parkinson\u2019s disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067771"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2174\/157488812798483421","article-title":"Liver growth factor promotes the survival of grafted neural stem cells in a rat model of Parkinson\u2019s disease","volume":"7","author":"Reimers","year":"2012","journal-title":"Curr. Stem. Cell Res. Ther."},{"key":"ref_11","first-page":"583","article-title":"The anti-fibrotic effect of liver growth factor is associated with decreased intrahepatic levels of matrix metalloproteinases 2 and 9 and transforming growth factor beta 1 in bile duct-ligated rats","volume":"23","author":"Rua","year":"2008","journal-title":"Histol. Histopathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/S0168-8278(99)80261-X","article-title":"Improvement in liver fibrosis, functionality and hemodynamics in CCI4-cirrhotic rats after injection of the Liver Growth Factor","volume":"30","author":"Munoz","year":"1999","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/S1579-2129(10)70005-7","article-title":"Liver growth factor improves pulmonary fibrosis secondary to cadmium administration in mice","volume":"46","year":"2010","journal-title":"Arch. Bronconeumol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Calatrava-Ferreras, L., Gonzalo-Gobernado, R., Reimers, D., Herranz, A.S., Casarejos, M.J., Jimenez-Escrig, A., Regadera, J., Velasco-Martin, J., Vallejo-Munoz, M., and Diaz-Gil, J.J. (2016). Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich\u2019s Ataxia Transgenic Mice. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122066"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19056","DOI":"10.3390\/ijms151019056","article-title":"Neuroprotective Role of Liver Growth Factor \u201cLGF\u201d in an Experimental Model of Cerebellar Ataxia","volume":"15","author":"Reimers","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s00702-010-0438-z","article-title":"Neuroinflammatory processes in Alzheimer\u2019s disease","volume":"117","author":"Heneka","year":"2010","journal-title":"J. Neural. Transm. (Vienna)"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3892\/br.2016.630","article-title":"Role of oxidative stress in Alzheimer\u2019s disease","volume":"4","author":"Huang","year":"2016","journal-title":"Biomed. Rep."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ejphar.2013.02.015","article-title":"Neuroprotective effects of salvianolic acid B on an Abeta25-35 peptide-induced mouse model of Alzheimer\u2019s disease","volume":"704","author":"Lee","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gonzalo-Gobernado, R., Reimers, D., Casarejos, M.J., Calatrava Ferreras, L., Vallejo-Munoz, M., Jimenez-Escrig, A., Diaz-Gil, J.J., Ulzurrun de Asanza, G.M., and Bazan, E. (2020). Liver Growth Factor Induces Glia-Associated Neuroprotection in an in Vitro Model of Parkinson\u2019s Disease. Brain Sci., 10.","DOI":"10.3390\/brainsci10050315"},{"key":"ref_21","first-page":"5","article-title":"Amyloid-beta Alzheimer targets\u2014Protein processing, lipid rafts, and amyloid-beta pores","volume":"89","author":"Arbor","year":"2016","journal-title":"Yale J. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1089\/ars.2012.5027","article-title":"Amyloid beta-peptide (1-42)-induced oxidative stress in Alzheimer disease: Importance in disease pathogenesis and progression","volume":"19","author":"Butterfield","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"435203","DOI":"10.1155\/2014\/435203","article-title":"Heat shock protein 70 in Alzheimer\u2019s disease","volume":"2014","author":"Lu","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5225","DOI":"10.1523\/JNEUROSCI.5478-10.2011","article-title":"Suppression of Alzheimer\u2019s disease-related phenotypes by expression of heat shock protein 70 in mice","volume":"31","author":"Hoshino","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_25","first-page":"609","article-title":"Sex-dependent effect of liver growth factor on atherosclerotic lesions and fatty liver disease in apolipoprotein E knockout mice","volume":"25","author":"Surra","year":"2010","journal-title":"Histol. Histopathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nrneurol.2010.157","article-title":"Alzheimer disease: Caspases first","volume":"6","author":"Avila","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1007\/s00018-007-7220-x","article-title":"Tauopathies","volume":"64","author":"Hernandez","year":"2007","journal-title":"Cell Mol. Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1073\/pnas.242720499","article-title":"Chaperones increase association of tau protein with microtubules","volume":"100","author":"Dou","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.4155\/fmc.11.88","article-title":"Molecular chaperones and regulation of tau quality control: Strategies for drug discovery in tauopathies","volume":"3","author":"Miyata","year":"2011","journal-title":"Future Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.brainresbull.2017.02.001","article-title":"Human astrocytes in the diseased brain","volume":"136","author":"Dossi","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3240","DOI":"10.1172\/JCI90606","article-title":"Microglia in Alzheimer\u2019s disease","volume":"127","author":"Sarlus","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/nan.12445","article-title":"Inflammatory pathology markers (activated microglia and reactive astrocytes) in early and late onset Alzheimer disease: A post mortem study","volume":"44","author":"Taipa","year":"2018","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_33","first-page":"124","article-title":"Microglial cell dysregulation in brain aging and neurodegeneration","volume":"7","author":"Eugenin","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1096\/fj.01-0530fje","article-title":"Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins","volume":"16","author":"Kakimura","year":"2002","journal-title":"FASEB J."},{"key":"ref_35","first-page":"123","article-title":"Microglia-astrocyte interaction in Alzheimer\u2019s disease: Friends or foes for the nervous system?","volume":"34","author":"Ramirez","year":"2001","journal-title":"Biol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/ni.2913","article-title":"The adaptor ASC has extracellular and \u2018prionoid\u2019 activities that propagate inflammation","volume":"15","author":"Franklin","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1016\/j.celrep.2020.02.025","article-title":"beta-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia","volume":"30","author":"Friker","year":"2020","journal-title":"Cell Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Scott, X.O., Stephens, M.E., Desir, M.C., Dietrich, W.D., Keane, R.W., and de Rivero Vaccari, J.P. (2020). The Inflammasome Adaptor Protein ASC in Mild Cognitive Impairment and Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134674"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nature25158","article-title":"Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer\u2019s disease","volume":"552","author":"Venegas","year":"2017","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12974-016-0477-y","article-title":"Activation of phagocytic activity in astrocytes by reduced expression of the inflammasome component ASC and its implication in a mouse model of Alzheimer disease","volume":"13","author":"Couturier","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1742-2094-11-48","article-title":"Microglia receptors and their implications in the response to amyloid beta for Alzheimer\u2019s disease pathogenesis","volume":"11","author":"Doens","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/acel.12522","article-title":"Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer\u2019s disease models: Effects of aging and amyloid pathology","volume":"16","author":"Martin","year":"2017","journal-title":"Aging Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0002-9440(10)64354-4","article-title":"CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer\u2019s disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils","volume":"160","author":"Coraci","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1016\/j.freeradbiomed.2004.01.007","article-title":"CD36 overexpression in human brain correlates with beta-amyloid deposition but not with Alzheimer\u2019s disease","volume":"36","author":"Ricciarelli","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"34914","DOI":"10.1074\/jbc.M111.232116","article-title":"A high content drug screen identifies ursolic acid as an inhibitor of amyloid beta protein interactions with its receptor CD36","volume":"286","author":"Wilkinson","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1097\/01.jnen.0000202887.22082.63","article-title":"Microglia in the aging brain","volume":"65","author":"Conde","year":"2006","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.bcp.2014.01.008","article-title":"Microglial dysfunction in brain aging and Alzheimer\u2019s disease","volume":"88","author":"Mosher","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1006\/bbrc.1997.6943","article-title":"An Nrf2\/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements","volume":"236","author":"Itoh","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.celrep.2019.06.047","article-title":"Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1","volume":"28","author":"Suzuki","year":"2019","journal-title":"Cell Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1128\/MCB.24.1.36-45.2004","article-title":"Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2)","volume":"24","author":"Itoh","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11624","DOI":"10.1038\/ncomms11624","article-title":"Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription","volume":"7","author":"Kobayashi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Kerr, F., Sofola-Adesakin, O., Ivanov, D.K., Gatliff, J., Gomez Perez-Nievas, B., Bertrand, H.C., Martinez, P., Callard, R., Snoeren, I., and Cocheme, H.M. (2017). Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer\u2019s disease. PLoS Genet, 13.","DOI":"10.1371\/journal.pgen.1006593"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11553","DOI":"10.1038\/s41598-018-29770-3","article-title":"Evidence supporting oxidative stress in a moderately affected area of the brain in Alzheimer\u2019s disease","volume":"8","author":"Youssef","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.neurobiolaging.2014.09.004","article-title":"Increased Alzheimer\u2019s disease-like pathology in the APP\/PS1DeltaE9 mouse model lacking Nrf2 through modulation of autophagy","volume":"36","author":"Joshi","year":"2015","journal-title":"Neurobiol. Aging."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.redox.2018.07.006","article-title":"Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy","volume":"18","author":"Rojo","year":"2018","journal-title":"Redox. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Uruno, A., Matsumaru, D., Ryoke, R., Saito, R., Kadoguchi, S., Saigusa, D., Saito, T., Saido, T.C., Kawashima, R., and Yamamoto, M. (2020). Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer\u2019s Disease Model Mice. Mol. Cell Biol., 40.","DOI":"10.1128\/MCB.00467-19"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1089\/ars.2014.5845","article-title":"CD36 upregulation mediated by intranasal LV-NRF2 treatment mitigates hypoxia-induced progression of Alzheimer\u2019s-like pathogenesis","volume":"21","author":"Wang","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Giron-Martinez, A., Perez-Rial, S., Terron-Exposito, R., Diaz-Gil, J.J., Gonzalez-Mangado, N., and Peces-Barba, G. (2014). Proliferative Activity of Liver Growth Factor is Associated with an Improvement of Cigarette Smoke-Induced Emphysema in Mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112995"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1042\/BST0341287","article-title":"Signalling molecules essential for neuronal survival and differentiation","volume":"34","author":"Frebel","year":"2006","journal-title":"Biochem. Soc. Trans."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1196\/annals.1299.113","article-title":"Increased apoptotic cell death in sporadic and genetic Alzheimer\u2019s disease","volume":"1010","author":"Eckert","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.freeradbiomed.2005.08.014","article-title":"Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer\u2019s disease","volume":"40","author":"Feng","year":"2006","journal-title":"Free Radic. Biol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.neulet.2012.10.043","article-title":"Protective effect of edaravone against Alzheimer\u2019s disease-relevant insults in neuroblastoma N2a cells","volume":"531","author":"Yan","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1007\/s11064-014-1454-4","article-title":"Apoptosis in Alzheimer\u2019s disease: An understanding of the physiology, pathology and therapeutic avenues","volume":"39","author":"Obulesu","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_64","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_65","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0002-9440(10)64544-0","article-title":"Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss","volume":"157","author":"Takeuchi","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1097\/00004647-200112000-00009","article-title":"Evidence of phosphorylation of Akt and neuronal survival after transient focal cerebral ischemia in mice","volume":"21","author":"Noshita","year":"2001","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1385\/MN:34:3:249","article-title":"Phosphoinositide-3-kinase\/akt survival signal pathways are implicated in neuronal survival after stroke","volume":"34","author":"Zhao","year":"2006","journal-title":"Mol. Neurobiol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Matsuda, S., Nakagawa, Y., Tsuji, A., Kitagishi, Y., Nakanishi, A., and Murai, T. (2018). Implications of PI3K\/AKT\/PTEN Signaling on Superoxide Dismutases Expression and in the Pathogenesis of Alzheimer\u2019s Disease. Diseases, 6.","DOI":"10.3390\/diseases6020028"},{"key":"ref_69","first-page":"299","article-title":"Activating Akt and the brain\u2019s resources to drive cellular survival and prevent inflammatory injury","volume":"20","author":"Chong","year":"2005","journal-title":"Histol. Histopathol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"21085","DOI":"10.1074\/jbc.M400063200","article-title":"Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils","volume":"279","author":"Gardai","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1002\/jnr.22670","article-title":"From the liver to the blood-brain barrier: An interconnected system regulating brain amyloid-beta levels","volume":"89","author":"Sagare","year":"2011","journal-title":"J. Neurosci. Res."},{"key":"ref_72","first-page":"1013","article-title":"Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs","volume":"44","author":"Thornalley","year":"1998","journal-title":"Cell Mol. Biol. (Noisy-Le-Grand)"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1016\/j.molimm.2003.11.027","article-title":"Expression of a novel secreted splice variant of the receptor for advanced glycation end products (RAGE) in human brain astrocytes and peripheral blood mononuclear cells","volume":"40","author":"Park","year":"2004","journal-title":"Mol. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1111\/nan.12440","article-title":"Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer\u2019s disease","volume":"43","author":"Wharton","year":"2017","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/nprot.2006.20","article-title":"Digging and marble burying in mice: Simple methods for in vivo identification of biological impacts","volume":"1","author":"Deacon","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"740","DOI":"10.3858\/emm.2012.44.12.082","article-title":"Expression of the plant viral protease NIa in the brain of a mouse model of Alzheimer\u2019s disease mitigates Abeta pathology and improves cognitive function","volume":"44","author":"Kim","year":"2012","journal-title":"Exp. Mol. Med."},{"key":"ref_77","first-page":"113","article-title":"Hepatic growth induced by injection of the liver growth factor into normal rats","volume":"4","author":"Rua","year":"1994","journal-title":"Growth Regul."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0378-4347(00)83660-9","article-title":"Quantitative fractionation of serum bilirubin species by reversed-phase high-performance liquid chromatography","volume":"380","author":"Singh","year":"1986","journal-title":"J. Chromatogr."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/hep.1840080308","article-title":"Identification of biliprotein as a liver growth factor","volume":"8","author":"Sanchez","year":"1988","journal-title":"Hepatology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1038\/nm1202-793","article-title":"Serum insulin-like growth factor I regulates brain amyloid-beta levels","volume":"8","author":"Carro","year":"2002","journal-title":"Nat. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"334","DOI":"10.2174\/156720512800107573","article-title":"Trehalose protects from aggravation of amyloid pathology induced by isoflurane anesthesia in APP(swe) mutant mice","volume":"9","author":"Perucho","year":"2012","journal-title":"Curr. Alzheimer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.expneurol.2009.09.029","article-title":"The effects of parkin suppression on the behaviour, amyloid processing, and cell survival in APP mutant transgenic mice","volume":"221","author":"Perucho","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"525","DOI":"10.3233\/JAD-130050","article-title":"Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy","volume":"35","author":"Casarejos","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"ref_84","unstructured":"Franklin, K., and Paxinos, G. (2007). The Mouse Brain in Stereotaxic Coordinates, Academic Press. [3rd ed.]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/9201\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:40:46Z","timestamp":1760179246000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/9201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,2]]},"references-count":84,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21239201"],"URL":"https:\/\/doi.org\/10.3390\/ijms21239201","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,2]]}}}