{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:25:28Z","timestamp":1781108728344,"version":"3.54.1"},"reference-count":49,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,17]],"date-time":"2020-04-17T00:00:00Z","timestamp":1587081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1D1A1B03033979"],"award-info":[{"award-number":["NRF-2017R1D1A1B03033979"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recently, an asymmetric vascular compromise approach that replicates many aspects of human vascular cognitive impairment (VCI) has been reported. The present study aimed to first investigate on the reproducibility in the disease progression of this newly reported VCI model using wild-type C57BL6\/J mice. The second aim was to assess how this approach will affect the disease progression of transgenic Alzheimer\u2019s disease (AD) 5XFAD mice subjected to VCI. C57BL6\/J and 5XFAD mice were subjected to VCI by placing an ameroid constrictor on the right CCA and a microcoil on the left CCA. Infarcts and hippocampal neuronal loss did not appear predominantly in the right (ameroid side) as expected but randomly in both hemispheres. The mortality rate of C57BL6\/J mice was unexpectedly high. Inducing VCI reduced amyloid burden in the hippocampi of 5XFAD mice. Since VCI is known to be complex and complicated, the heterogeneous disease progression observed from this current study shares close resemblance to the clinical manifestation of VCI. This heterogeneity, however, makes it challenging to test novel treatment options using this model. Further study is warranted to tackle the heterogeneous nature of VCI.<\/jats:p>","DOI":"10.3390\/ijms21082820","type":"journal-article","created":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T04:49:38Z","timestamp":1587444578000},"page":"2820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Heterogeneous Disease Progression in a Mouse Model of Vascular Cognitive Impairment"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6116-2562","authenticated-orcid":false,"given":"Na Kyung","family":"Lee","sequence":"first","affiliation":[{"name":"School of Medicine, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"},{"name":"Stem Cell &amp; Regenerative Medicine Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"},{"name":"Samsung Alzheimer Research Center, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunnyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory Animal Research Center, Samsung Biomedical Research Institute, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jehoon","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory Animal Research Center, Samsung Biomedical Research Institute, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory Animal Research Center, Samsung Biomedical Research Institute, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Pyo","family":"Son","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center, Osong Medical Innovation Foundation, Cheongju 28160, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyemin","family":"Jang","sequence":"additional","affiliation":[{"name":"Stem Cell &amp; Regenerative Medicine Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"},{"name":"Samsung Alzheimer Research Center, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"},{"name":"Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duk L.","family":"Na","sequence":"additional","affiliation":[{"name":"Stem Cell &amp; Regenerative Medicine Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"},{"name":"Samsung Alzheimer Research Center, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"},{"name":"Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"},{"name":"Neuroscience Center, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"},{"name":"Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hainsworth, A.H., Allan, S.M., Boltze, J., Cunningham, C., Farris, C., Head, E., Ihara, M., Isaacs, J.D., Kalaria, R.N., and Lesnik Oberstein, S.A. (2017). Translational models for vascular cognitive impairment: A review including larger species. BMC Med., 15.","DOI":"10.1186\/s12916-017-0793-9"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e002757","DOI":"10.1161\/JAHA.115.002757","article-title":"Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans","volume":"5","author":"Hattori","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.bbadis.2015.12.009","article-title":"Vascular cognitive impairment: Modeling a critical neurologic disease in vitro and in vivo","volume":"1862","author":"Helman","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1212\/WNL.0b013e318221acee","article-title":"Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B","volume":"77","author":"Lee","year":"2011","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s10571-015-0286-3","article-title":"Animal Models of Vascular Cognitive Impairment and Dementia (VCID)","volume":"36","author":"Gooch","year":"2016","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1042\/CS20160727","article-title":"Chronic cerebral hypoperfusion: A key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia","volume":"131","author":"Duncombe","year":"2017","journal-title":"Clin. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1523\/JNEUROSCI.3970-14.2015","article-title":"A novel mouse model of subcortical infarcts with dementia","volume":"35","author":"Hattori","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hattori, Y., Kitamura, A., Nagatsuka, K., and Ihara, M. (2014). A novel mouse model of ischemic carotid artery disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100257"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Roberts, J.M., Maniskas, M.E., and Bix, G.J. (2018). Bilateral carotid artery stenosis causes unexpected early changes in brain extracellular matrix and blood-brain barrier integrity in mice. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0195765"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1161\/STROKEAHA.110.581686","article-title":"A mouse model characterizing features of vascular dementia with hippocampal atrophy","volume":"41","author":"Nishio","year":"2010","journal-title":"Stroke"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"978761","DOI":"10.4061\/2011\/978761","article-title":"Lessons from a mouse model characterizing features of vascular cognitive impairment with white matter changes","volume":"2011","author":"Ihara","year":"2011","journal-title":"J. Aging Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"32179","DOI":"10.1038\/srep32179","article-title":"Substantial Reduction of Parenchymal Cerebral Blood Flow in Mice with Bilateral Common Carotid Artery Stenosis","volume":"6","author":"Hattori","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11864","DOI":"10.18632\/oncotarget.7689","article-title":"Severe chronic cerebral hypoperfusion induces microglial dysfunction leading to memory loss in APPswe\/PS1 mice","volume":"7","author":"Bordeleau","year":"2016","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14102","DOI":"10.1038\/s41598-019-50681-4","article-title":"The effect of chronic cerebral hypoperfusion on the pathology of Alzheimer\u2019s disease: A positron emission tomography study in rats","volume":"9","author":"Park","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.2217\/fnl.13.66","article-title":"Optimizing mouse models of neurodegenerative disorders: Are therapeutics in sight?","volume":"9","author":"Lutz","year":"2013","journal-title":"Future Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23964","DOI":"10.1038\/srep23964","article-title":"Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer\u2019s disease mice","volume":"6","author":"Qiu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.bbadis.2015.12.023","article-title":"Vascular contributions to cognitive impairment, clinical Alzheimer\u2019s disease, and dementia in older persons","volume":"1862","author":"Kapasi","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1172\/JCI97509","article-title":"Blood will out: Vascular contributions to Alzheimer\u2019s disease","volume":"128","author":"Strickland","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1242\/dev.116.1.201","article-title":"NeuN, a neuronal specific nuclear protein in vertebrates","volume":"116","author":"Mullen","year":"1992","journal-title":"Development"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0006-8993(96)01453-9","article-title":"C57BL\/6 strain is most susceptible to cerebral ischemia following bilateral common carotid occlusion among seven mouse strains: Selective neuronal death in the murine transient forebrain ischemia","volume":"752","author":"Yang","year":"1997","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1161\/01.STR.31.11.2707","article-title":"Differences in vulnerability to permanent focal cerebral ischemia among 3 common mouse strains","volume":"31","author":"Majid","year":"2000","journal-title":"Stroke"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1161\/CIRCRESAHA.116.308426","article-title":"Vascular Cognitive Impairment","volume":"120","author":"Dichgans","year":"2017","journal-title":"Circ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s00401-004-0864-9","article-title":"Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain","volume":"108","author":"Farkas","year":"2004","journal-title":"Acta Neuropathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1177\/0271678X17713105","article-title":"Dimethyl fumarate improves white matter function following severe hypoperfusion: Involvement of microglia\/macrophages and inflammatory mediators","volume":"38","author":"Fowler","year":"2018","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1161\/01.STR.32.5.1208","article-title":"Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain","volume":"32","author":"Ito","year":"2001","journal-title":"Stroke"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.brainresrev.2007.01.003","article-title":"Permanent, bilateral common carotid artery occlusion in the rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases","volume":"54","author":"Farkas","year":"2007","journal-title":"Brain Res. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1161\/01.STR.0000143725.19053.60","article-title":"White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion","volume":"35","author":"Shibata","year":"2004","journal-title":"Stroke"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"301","DOI":"10.4196\/kjpp.2018.22.3.301","article-title":"Atorvastatin pretreatment attenuates kainic acid-induced hippocampal neuronal death via regulation of lipocalin-2-associated neuroinflammation","volume":"22","author":"Jin","year":"2018","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"322","DOI":"10.3389\/fnagi.2014.00322","article-title":"The neuron-astrocyte-microglia triad in a rat model of chronic cerebral hypoperfusion: Protective effect of dipyridamole","volume":"6","author":"Lana","year":"2014","journal-title":"Front. Aging Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14515","DOI":"10.1073\/pnas.0406344101","article-title":"Spatial memory, recognition memory, and the hippocampus","volume":"101","author":"Broadbent","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9697","DOI":"10.1073\/pnas.92.21.9697","article-title":"Spatial learning with a minislab in the dorsal hippocampus","volume":"92","author":"Moser","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/jcbfm.2014.221","article-title":"Vascular change and opposing effects of the angiotensin type 2 receptor in a mouse model of vascular cognitive impairment","volume":"35","author":"Fuchtemeier","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1161\/STROKEAHA.116.014394","article-title":"Neuroimaging Biomarkers Predict Brain Structural Connectivity Change in a Mouse Model of Vascular Cognitive Impairment","volume":"48","author":"Fuchtemeier","year":"2017","journal-title":"Stroke"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9541","DOI":"10.1038\/s41598-017-10074-x","article-title":"Correlations between Gray Matter and White Matter Degeneration in Pure Alzheimer\u2019s Disease, Pure Subcortical Vascular Dementia, and Mixed Dementia","volume":"7","author":"Jang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.neuroimage.2006.04.187","article-title":"Diffusion tensor imaging of time-dependent axonal and myelin degradation after corpus callosotomy in epilepsy patients","volume":"32","author":"Concha","year":"2006","journal-title":"Neuroimage"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13195-015-0104-7","article-title":"Clinical and imaging features of mixed Alzheimer and vascular pathologies","volume":"7","author":"Chui","year":"2015","journal-title":"Alzheimers Res. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Attems, J., and Jellinger, K.A. (2014). The overlap between vascular disease and Alzheimer\u2019s disease\u2014Lessons from pathology. BMC Med., 12.","DOI":"10.1186\/s12916-014-0206-2"},{"key":"ref_38","first-page":"69","article-title":"Pathophysiologic relationship between Alzheimer\u2019s disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis","volume":"7","author":"Santos","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","unstructured":"Yamada, M., Ihara, M., Okamoto, Y., Maki, T., Washida, K., Kitamura, A., Hase, Y., Ito, H., Takao, K., and Miyakawa, T. (2011). The influence of chronic cerebral hypoperfusion on cognitive function and amyloid beta metabolism in APP overexpressing mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016567"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1042\/CS20170962","article-title":"Chronic cerebral hypoperfusion alters amyloid-beta peptide pools leading to cerebral amyloid angiopathy, microinfarcts and haemorrhages in Tg-SwDI mice","volume":"131","author":"Salvadores","year":"2017","journal-title":"Clin. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/j.1552-6569.2011.00610.x","article-title":"Hippocampus: A \u201cforgotten\u201d border zone of brain ischemia","volume":"23","author":"Walha","year":"2013","journal-title":"J. Neuroimaging"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s12975-017-0590-y","article-title":"MRI Guiding of the Middle Cerebral Artery Occlusion in Rats Aimed to Improve Stroke Modeling","volume":"9","author":"Gubskiy","year":"2018","journal-title":"Transl. Stroke Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"256","DOI":"10.3171\/jns.1993.79.2.0256","article-title":"Microsurgical anatomy of the hippocampal arteries","volume":"79","author":"Erdem","year":"1993","journal-title":"J. Neurosurg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nm0204-117","article-title":"Specificity of mechanisms for plaque removal after A beta immunotherapy for Alzheimer disease","volume":"10","author":"Akiyama","year":"2004","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e262","DOI":"10.21769\/BioProtoc.262","article-title":"Mouse Transient Global Ischemia Two-Vessel Occlusion Model","volume":"2","author":"Pontarelli","year":"2012","journal-title":"Bio Protoc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s12015-016-9694-0","article-title":"Magnetic Resonance Imaging of Ferumoxytol-Labeled Human Mesenchymal Stem Cells in the Mouse Brain","volume":"13","author":"Lee","year":"2017","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lee, N.K., Yang, J., Chang, E.H., Park, S.E., Lee, J., Choi, S.J., Oh, W., Chang, J.W., and Na, D.L. (2016). Intra-Arterially Delivered Mesenchymal Stem Cells Are Not Detected in the Brain Parenchyma in an Alzheimer\u2019s Disease Mouse Model. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155912"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4926815","DOI":"10.1155\/2017\/4926815","article-title":"Amelioration of Scopolamine-Induced Learning and Memory Impairment by alpha-Pinene in C57BL\/6 Mice","volume":"2017","author":"Lee","year":"2017","journal-title":"Evid. Based Complement. Alternat. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/2820\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:08:58Z","timestamp":1760364538000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/2820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,17]]},"references-count":49,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21082820"],"URL":"https:\/\/doi.org\/10.3390\/ijms21082820","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,17]]}}}