{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T01:47:56Z","timestamp":1787104076757,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T00:00:00Z","timestamp":1588723200000},"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-2017S1A5A2A01024208"],"award-info":[{"award-number":["NRF-2017S1A5A2A01024208"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease is the most common neurodegenerative brain disease causing dementia. It is characterized by slow onset and gradual worsening of memory and other cognitive functions. Recently, parabiosis and infusion of plasma from young mice have been proposed to have positive effects in aging and Alzheimer\u2019s disease. Therefore, this study examined whether infusion of plasma from exercised mice improved cognitive functions related to the hippocampus in a 3xTg-Alzheimer\u2019s disease (AD) model. We collected plasma from young mice that had exercised for 3 months and injected 100 \u00b5L of plasma into the tail vein of 12-month-old 3xTg-AD mice 10 times at 3-day intervals. We then analyzed spatial learning and memory, long-term memory, hippocampal GSK3\u03b2\/tau proteins, synaptic proteins, mitochondrial function, apoptosis, and neurogenesis. In the hippocampus of 3xTg-AD mice, infusion of plasma from exercised mice improved neuroplasticity and mitochondrial function and suppressed apoptosis, ultimately improving cognitive function. However, there was no improvement in tau hyperphosphorylation. This study showed that plasma from exercised mice could have a protective effect on cognitive dysfunction and neural circuits associated with AD via a tau-independent mechanism involving elevated brain-derived neurotrophic factor due to exercise.<\/jats:p>","DOI":"10.3390\/ijms21093291","type":"journal-article","created":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T03:10:38Z","timestamp":1588821038000},"page":"3291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Infusion of Plasma from Exercised Mice Ameliorates Cognitive Dysfunction by Increasing Hippocampal Neuroplasticity and Mitochondrial Functions in 3xTg-AD Mice"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8832-0874","authenticated-orcid":false,"given":"Tae-Woon","family":"Kim","sequence":"first","affiliation":[{"name":"Exercise Rehabilitation Research Institute, Department of Exercise &amp; Health Science, Sangmyung University, Seoul 03016, Korea"},{"name":"Department of Physiology, College of Medicine, KyungHee University, Seoul 02447, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Seo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, KyungHee University, Seoul 02447, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon-Young","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, College of Public Health and Cardiovascular Research Center, Lewis Katz school of Medicine, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Sang","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, College of Public Health and Cardiovascular Research Center, Lewis Katz school of Medicine, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/nature02621","article-title":"Pathways towards and away from Alzheimer\u2019s disease","volume":"430","author":"Mattson","year":"2004","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.expneurol.2009.01.011","article-title":"The Alzheimer\u2019s disease mitochondrial cascade hypothesis: An update","volume":"218","author":"Swerdlow","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.pharep.2014.09.004","article-title":"A review on Alzheimer\u2019s disease pathophysiology and its management: An update","volume":"67","author":"Kumar","year":"2015","journal-title":"Pharmacol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0140-6736(06)69113-7","article-title":"Alzheimer\u2019s disease","volume":"368","author":"Blennow","year":"2006","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00401-009-0536-x","article-title":"Synaptic degeneration in Alzheimer\u2019s disease","volume":"118","author":"Arendt","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.nlm.2007.05.001","article-title":"Neurogenesis decreases with age in the canine hippocampus and correlates with cognitive function","volume":"88","author":"Head","year":"2007","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1083\/jcb.200108057","article-title":"Taublockstraffic of organelles, neurofilaments, and APPvesicles in neurons and enhance soxidativestress","volume":"156","author":"Stamer","year":"2002","journal-title":"Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.neurobiolaging.2003.04.007","article-title":"Clogging of axons by tau, inhibition of axonaltraffic and starvation of synapses","volume":"24","author":"Mandelkow","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/cm.20243","article-title":"Tau inhibits anterograde axonal transport and perturbs stability in growing axonal neurites in part by displacing kinesin cargo: Neurofilaments attenuate tau-mediated neurite instability","volume":"65","author":"Dubey","year":"2008","journal-title":"Cell Motil. Cytoskelet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/jnc.14829","article-title":"The energetic brain\u2014A review from students to students","volume":"151","author":"Bordone","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1007\/s007020050099","article-title":"Abnormalities of mitochondrial enzymes in Alzheimer disease","volume":"105","author":"Gibson","year":"1998","journal-title":"J. Neural Transm. (Vienna)"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9057","DOI":"10.1523\/JNEUROSCI.1469-06.2006","article-title":"Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer\u2019s disease brain is associated with mitochondrial dysfunction","volume":"26","author":"Devi","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1212\/WNL.40.8.1302","article-title":"Cytochrome oxidase deficiency in Alzheimer\u2019s disease","volume":"40","author":"Parker","year":"1990","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19318","DOI":"10.1073\/pnas.0804871105","article-title":"Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission\/fusion proteins","volume":"105","author":"Wang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/nm.3569","article-title":"Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice","volume":"20","author":"Villeda","year":"2014","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.physbeh.2010.09.021","article-title":"Treadmill exercise inhibits traumatic brain injury-induced hippocampal apoptosis","volume":"101","author":"Kim","year":"2010","journal-title":"Physiol. Behav."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1002\/jnr.21317","article-title":"Voluntary exercise-induced neurogenesis in the postischemic dentate gyrus is associated with spatial memory recovery from stroke","volume":"85","author":"Luo","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ke, Z., Yip, S.P., Li, L., Zheng, X.X., and Tong, K.Y. (2011). The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: A rat brain ischemia model. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016643"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1017\/S0317167100007769","article-title":"Mild to moderate early exercise promotes recovery from cerebral ischemia in rats","volume":"36","author":"Lee","year":"2009","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_20","first-page":"119","article-title":"Endurance training increases plasma brain-derived neurotrophic factor concentration in young healthy men","volume":"7","author":"Zoladz","year":"2008","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R372","DOI":"10.1152\/ajpregu.00525.2009","article-title":"Endurance training enhances BDNF release from the human brain","volume":"298","author":"Seifert","year":"2010","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"386","DOI":"10.3389\/fncel.2017.00386","article-title":"Transcriptome Analysis of Gene Expression Provides New Insights into the Effect of Mild Therapeutic Hypothermia on Primary Human Cortical Astrocytes Cultured under Hypoxia","volume":"11","author":"Salman","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"797","DOI":"10.3389\/fneur.2018.00797","article-title":"Elucidating the Interactive Roles of Glia in Alzheimer\u2019s Disease Using Established and Newly Developed Experimental Models","volume":"9","author":"Chun","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S0896-6273(03)00434-3","article-title":"Triple-transgenic model of Alzheimer\u2019s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction","volume":"39","author":"Oddo","year":"2003","journal-title":"Neuron"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13357","DOI":"10.1523\/JNEUROSCI.2718-07.2007","article-title":"Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice","volume":"27","author":"Carroll","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.brainres.2011.07.052","article-title":"Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer\u2019s disease","volume":"1415","author":"Reddy","year":"2011","journal-title":"Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1016\/j.bbabio.2008.07.004","article-title":"A peptide containing residues 26\u201344 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator","volume":"1777","author":"Atlante","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1111\/j.1471-4159.2007.04626.x","article-title":"Calcium-induced precipitate formation in brain mitochondria: Composition, calcium capacity, and retention","volume":"102","author":"Kristian","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s10495-006-0525-7","article-title":"Role of the mitochondrial membrane permeability transition in cell death","volume":"12","author":"Tsujimoto","year":"2007","journal-title":"Apoptosis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nature10357","article-title":"The ageing systemic milieu negatively regulates neurogenesis and cognitive function","volume":"477","author":"Villeda","year":"2011","journal-title":"Nature"},{"key":"ref_32","first-page":"39","article-title":"Young plasma ameliorates aging-related acute brain injury after intracerebral hemorrhage","volume":"17","author":"Yuan","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1001\/jamaneurol.2016.3185","article-title":"Preclinical Assessment of Young Blood Plasma for Alzheimer Disease","volume":"73","author":"Middeldorp","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_34","first-page":"1","article-title":"Exercise training increases cardiac, hepatic and circulating levels of brain-derived neurotrophic factor and irisin in young and aged rats","volume":"36","author":"Okudan","year":"2018","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.neulet.2013.12.034","article-title":"Effect of fat free mass on serum and plasma BDNF concentrations during exercise and recovery in healthy young men","volume":"560","author":"Gilder","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/mp.2016.62","article-title":"Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer\u2019s disease: A meta-analysis study (N = 7277)","volume":"22","author":"Qin","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s00702-013-1121-y","article-title":"Plasma BDNF levels are correlated with aggressiveness in patients with amnestic mild cognitive impairment or Alzheimer disease","volume":"121","author":"Nagata","year":"2014","journal-title":"J. Neural. Transm. (Vienna)"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1017\/S1461145710000738","article-title":"Blood BDNF concentrations reflect brain-tissue BDNF levels across species","volume":"14","author":"Klein","year":"2011","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nm.1912","article-title":"Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer\u2019s disease","volume":"15","author":"Nagahara","year":"2009","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e907","DOI":"10.1038\/tp.2016.186","article-title":"Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer\u2019s disease","volume":"6","author":"Jiao","year":"2016","journal-title":"Transl. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1523\/JNEUROSCI.3741-04.2005","article-title":"Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus","volume":"25","author":"Sairanen","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1006\/nbdi.1999.0275","article-title":"BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia","volume":"7","author":"Han","year":"2000","journal-title":"Neurobiol. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1111\/j.1460-9568.2004.03578.x","article-title":"BDNF increases rat brain mitochondrial respiratory coupling at complex I, but not complex II","volume":"20","author":"Markham","year":"2004","journal-title":"Eur. J. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/9\/3291\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:25:59Z","timestamp":1760174759000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/9\/3291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,6]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ijms21093291"],"URL":"https:\/\/doi.org\/10.3390\/ijms21093291","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,6]]}}}