{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T02:32:38Z","timestamp":1768530758746,"version":"3.49.0"},"reference-count":75,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,4,4]],"date-time":"2017-04-04T00:00:00Z","timestamp":1491264000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Natural Scientific Foundation, China","award":["81170322, 81571361"],"award-info":[{"award-number":["81170322, 81571361"]}]},{"name":"Shanghai Natural Scientific Foundation, China","award":["11ZR1405300"],"award-info":[{"award-number":["11ZR1405300"]}]},{"name":"Shanghai Municipal Outstanding Talent Development Foundation","award":["2012052"],"award-info":[{"award-number":["2012052"]}]},{"name":"Taishan Scholars Program","award":["TSQN20161070"],"award-info":[{"award-number":["TSQN20161070"]}]},{"name":"Science and Technology Development Plan of Shandong Province, China","award":["2014GSF118046"],"award-info":[{"award-number":["2014GSF118046"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2017,6]]},"abstract":"Summary<\/jats:title>Aims<\/jats:title>Although cognitive dysfunction is a common neurological complication in elderly patients with diabetes, the mechanisms underlying this relationship remain unclear, and effective preventive interventions have yet to be developed. Thus, this study investigated the preventive effects and mechanisms of action associated with granulocyte colony\u2010stimulating factor (G\u2010CSF<\/jats:styled-content>) on cognitive dysfunction in elderly diabetic mice with cerebral small vessel disease.<\/jats:p><\/jats:sec>Methods<\/jats:title>This study included 40 male db\/db diabetic and wild\u2010type (WT<\/jats:styled-content>) mice that were categorized into the following four groups at the age of 3\u00a0weeks: db\/db group (DG<\/jats:styled-content>), db\/db+G\u2010CSF<\/jats:styled-content> group (DGG<\/jats:styled-content>), WT<\/jats:styled-content> group (WG<\/jats:styled-content>), and WT<\/jats:styled-content>+G\u2010CSF<\/jats:styled-content> group (WGG<\/jats:styled-content>). The mice were fed normal diets for 4\u00a0months and then given G\u2010CSF<\/jats:styled-content> (75\u00a0\u03bcg\/kg) via intraperitoneal injections for 1\u00a0month. At 7.5\u00a0months of age, the cognitive abilities of the mice were assessed with the Y\u2010maze test and the Social Choice Test; body weight, blood pressure (BP<\/jats:styled-content>), and blood glucose measurements were obtained throughout the study. Brain imaging and blood oxygen level\u2010dependent (BOLD<\/jats:styled-content>) contrast imaging analyses were performed with a small animal magnetic resonance imaging (MRI<\/jats:styled-content>) system, autophagosome levels were detected with a transmission electron microscope (TEM<\/jats:styled-content>), hippocampal neurons were assessed with hematoxylin and eosin (HE<\/jats:styled-content>) staining, and protein expressions and distributions were evaluated using immunohistochemistry and Western blot analyses.<\/jats:p><\/jats:sec>Results<\/jats:title>(i) The body weight and blood glucose levels of the DG<\/jats:styled-content> and DGG<\/jats:styled-content> mice were significantly higher than those of the WG<\/jats:styled-content> and WGG<\/jats:styled-content> mice; (ii) social choice and spatial memory capabilities were significantly reduced in DG<\/jats:styled-content> mice but were recovered by G\u2010CSF<\/jats:styled-content> in DGG<\/jats:styled-content> mice; (iii) the MRI<\/jats:styled-content> scans revealed multiple lacunar lesions and apparent hippocampal atrophy in the brains of DG<\/jats:styled-content> mice, but G\u2010CSF<\/jats:styled-content> reduced the number of lacunar lesions and ameliorated hippocampal atrophy; (iv) the MRI<\/jats:styled-content>\u2010BOLD<\/jats:styled-content> scans showed a downward trend in whole\u2010brain activity and reductions in the connectivities of the hippocampus and amygdala with subcortical structures in DG<\/jats:styled-content> mice, but G\u2010CSF<\/jats:styled-content> clearly improved the altered brain activity as well as the connectivity of the hippocampus in DGG<\/jats:styled-content> mice; (v) HE<\/jats:styled-content> staining revealed fewer neurons in the hippocampus in DG<\/jats:styled-content> mice; (vi) TEM<\/jats:styled-content> analyses revealed significantly fewer autophagosomes in the hippocampi of DG<\/jats:styled-content> mice, but G\u2010CSF<\/jats:styled-content> did not increase these numbers; (vii) there were significant reductions in mechanistic target of rapamycin (mTOR<\/jats:styled-content>) and LC<\/jats:styled-content>3\u2010phosphatidylethanolamine conjugate (LC<\/jats:styled-content>3)\u2010II<\/jats:styled-content>\/I levels in the hippocampi of DG<\/jats:styled-content> mice, whereas p62 was upregulated, and G\u2010CSF<\/jats:styled-content> significantly enhanced the levels of Beclin1, mTOR<\/jats:styled-content>, and LC<\/jats:styled-content>\u2010II<\/jats:styled-content>\/I in DGG<\/jats:styled-content> mice; and (viii) G\u2010CSF<\/jats:styled-content> significantly reversed increases in nuclear factor \u03baB (NF<\/jats:styled-content>\u2010\u03baB) protein levels in DG<\/jats:styled-content> but not in WG<\/jats:styled-content> mice.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>In this study, aged diabetic mice were prone to cognitive dysfunction and cerebral small vessel disease. However, administration of G\u2010CSF<\/jats:styled-content> significantly improved cognitive function in elderly db\/db diabetic mice, and this change was likely related to the regulation of autophagy and NF<\/jats:styled-content>\u2010\u03baB signaling pathways.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.12691","type":"journal-article","created":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T15:42:50Z","timestamp":1491406970000},"page":"462-474","source":"Crossref","is-referenced-by-count":23,"title":["G\u2010CSF<\/scp> and cognitive dysfunction in elderly diabetic mice with cerebral small vessel disease: Preventive intervention effects and underlying mechanisms"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0778-6483","authenticated-orcid":false,"given":"Zhu\u2010Fei","family":"Guan","sequence":"first","affiliation":[{"name":"Department of Geriatric Neurology Huashan Hospital Fudan University Shanghai China"},{"name":"State Key Laboratory of Medical Neurobiology Institute of Brain Science Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying\u2010Hong","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of General Medicine Ouyang Community Health Service Center Hongkou District Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao\u2010Ming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Neurology Huashan Hospital Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi\u2010Lin","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology Institute of Brain Science Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying\u2010Chao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shandong Provincial Hospital Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Neurology Huashan Hospital Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan\u2010Mei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Neurology Huashan Hospital Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"ji","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology Institute of Brain Science Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo\u2010Feng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Emergency Neurology Affiliated Hospital Guiyang Medical University Guiyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na\u2010Na","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Neurology Huashan Hospital Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Neurology Huashan Hospital Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong\u2010Yu","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Geriatric Neurology Huashan Hospital Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing\u2010Chun","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology Institute of Brain Science Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hou\u2010Guang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Geriatric Neurology Huashan Hospital Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,4,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00417687"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00075197-200209000-00016"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.2174\/187152709789824651"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2006"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb0311-184"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12268"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07976"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.15.1178"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.1.13044"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2004.05.007"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000149519.47454.F2"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/60.4.471"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1922.00110120086003"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.10.026"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.019265"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2010.02.008"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.01.021"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2008.10.016"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.2174\/18715281113129990053"},{"key":"e_1_2_8_21_1","first-page":"532","article-title":"Tissue specific role of calcium\u2010sensing receptor","volume":"18","author":"Sarkar P","year":"2014","journal-title":"Atlas Genet Cytogenet Oncol Haematol"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11830"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.18.1.621"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000142616.07367.66"},{"key":"e_1_2_8_25_1","first-page":"1371","article-title":"G\u2010CSF protects human brain vascular endothelial cells injury induced by high glucose, free fatty acids and hypoxia through MAPK and Akt signaling","volume":"10","author":"Su JJ","year":"2015","journal-title":"PLoS One"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1824"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-1848.2004.00076.x"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.2000.0586"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.55.11.1626"},{"key":"e_1_2_8_30_1","first-page":"316","article-title":"Reduced hippocampal volume correlates with executive dysfunctioning in major depression","volume":"31","author":"Frodl T","year":"2006","journal-title":"J Psychiatry Neurosci"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12068"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.55.10.967"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000104524.25807.EE"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.10.041"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1042\/bse0550001"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.19496"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00030.2009"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2013.05.007"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.12.014"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601623"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.02.001"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.057"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.3930"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.2229"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12123"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.135329"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.3268"},{"key":"e_1_2_8_48_1","first-page":"2190","article-title":"The autophagy\u2010related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid accumulation in mice","volume":"118","author":"Pickford F","year":"2008","journal-title":"J Clin Invest"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2010.01.001"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.632"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01257917"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2010.258"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-006-0221-8"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.100420"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009979"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64209"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09663"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2010.12.009"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018666"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.254417"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100390"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12441"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2009.12.012"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.109.575621"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-7091-0693-8_44"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1179\/016164110X12807570510013"},{"key":"e_1_2_8_67_1","first-page":"333","article-title":"Influence of granulocyte\u2010colony stimulating factor on distribution of bone marrow stem cells and its role in protecting brain in rats with cerebral ischemia","volume":"23","author":"Li JS","year":"2011","journal-title":"Chin Crit Care Med"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2011.04.018"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-011-0608-2"},{"key":"e_1_2_8_70_1","first-page":"5207","article-title":"Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke","volume":"24","author":"Bath PM","year":"2013","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.113.001531"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.110.597799"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1159\/000335869"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2009.07.077"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1002\/gps.2572"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11596-012-1050-2"}],"container-title":["CNS Neuroscience & Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcns.12691","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.12691","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T18:16:27Z","timestamp":1696356987000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.12691"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,4]]},"references-count":75,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017,6]]}},"alternative-id":["10.1111\/cns.12691"],"URL":"https:\/\/doi.org\/10.1111\/cns.12691","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,4]]}}}