{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:45:35Z","timestamp":1790394335477,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2016,8,24]],"date-time":"2016-08-24T00:00:00Z","timestamp":1471996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is the most common form of dementia, yet there are no therapeutic treatments that can either cure or delay its onset. Currently, the pathogenesis of AD is still uncertain, especially with respect to how the disease develops from a normal healthy brain. Amyloid \u03b2 oligomers (A\u03b2O) are highly neurotoxic proteins and are considered potential initiators to the pathogenesis of AD. Rat brains were exposed to A\u03b2O via bilateral intracerebroventricular injections. Rats were then euthanized at either 1, 3, 7 or 21-days post surgery. Rat behavioural testing was performed using the Morris water maze and open field tests. Post-mortem brain tissue was immunolabelled for A\u03b2, microglia, and cholinergic neurons. Rats exposed to A\u03b2O showed deficits in spatial learning and anxiety-like behaviour. Acute positive staining for A\u03b2 was only observed in the corpus callosum surrounding the lateral ventricles. A\u03b2O exposed rat brains also showed a delayed increase in activated microglia within the corpus callosum and a decreased number of cholinergic neurons within the basal forebrain. Acute exposure to A\u03b2O resulted in mild learning and memory impairments with co-concomitant white matter pathology within the corpus callosum and cholinergic cell loss within the basal forebrain. Results suggest that acute exposure to A\u03b2O in the rat may be a useful tool in assessing the early phases for the pathogenesis of AD.<\/jats:p>","DOI":"10.3390\/ijms17091390","type":"journal-article","created":{"date-parts":[[2016,8,24]],"date-time":"2016-08-24T09:59:47Z","timestamp":1472032787000},"page":"1390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Assessing the Effects of Acute Amyloid \u03b2 Oligomer Exposure in the Rat"],"prefix":"10.3390","volume":"17","author":[{"given":"Ryan","family":"Wong","sequence":"first","affiliation":[{"name":"Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Cechetto","sequence":"additional","affiliation":[{"name":"Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Whitehead","sequence":"additional","affiliation":[{"name":"Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Haass, C., Kaether, C., Thinakaran, G., and Sisodia, S. (2012). Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med., 2.","DOI":"10.1101\/cshperspect.a006270"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1126\/science.1439760","article-title":"Production of the Alzheimer amyloid \u03b2 protein by normal proteolytic processing","volume":"258","author":"Shoji","year":"1992","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/359325a0","article-title":"Isolation and quantification of soluble Alzheimer\u2019s \u03b2-peptide from biological fluids","volume":"359","author":"Seubert","year":"1992","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/359322a0","article-title":"Amyloid \u03b2 peptide is produced by cultured cells during normal metabolism","volume":"359","author":"Haass","year":"1992","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8729","DOI":"10.1073\/pnas.82.24.8729","article-title":"Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related","volume":"82","author":"Wong","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrm2101","article-title":"Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer\u2019s amyloid \u03b2-peptide","volume":"8","author":"Haass","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/325733a0","article-title":"The precursor of Alzheimer\u2019s disease amyloid A4 protein resembles a cell-surface receptor","volume":"325","author":"Kang","year":"1987","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/0092-8674(93)90312-E","article-title":"Cellular processing of \u03b2-amyloid precursor protein and the genesis of amyloid \u03b2-peptide","volume":"75","author":"Haass","year":"1993","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.nbd.2008.01.010","article-title":"A\u03b2-globulomers are formed independently of the fibril pathway","volume":"30","author":"Gellermann","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nsmb.1799","article-title":"Structural conversion of neurotoxic amyloid-\u03b21\u201342 oligomers to fibrils","volume":"17","author":"Ahmed","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12451","DOI":"10.1021\/bi701213s","article-title":"Amyloid-B1\u201342 rapidly forms protofibrils and oligomers by distinct pathways in low concentrations of sodium dodecylsulfate","volume":"46","author":"Rangachari","year":"2007","journal-title":"Biochemistry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: Amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/S0006-291X(84)80190-4","article-title":"Alzheimer\u2019s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein","volume":"120","author":"Glenner","year":"1984","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","first-page":"353","article-title":"The amyloid hypothesis of Alzheimer\u2019s Disease: Progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Sci. Compass Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/ca.980080612","article-title":"An English translation of Alzheimer\u2019s 1907 paper, \u201cuber eine eigenartige erkankung der hirnrinde\u201d","volume":"8","author":"Stelzmann","year":"1995","journal-title":"Clin. Anat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10417","DOI":"10.1073\/pnas.1834302100","article-title":"Alzheimer\u2019s disease-affected brain: Presence of oligomeric A \u03b2 ligands (ADDLs) suggests a molecular basis for reversible memory loss","volume":"100","author":"Gong","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.phrs.2003.12.028","article-title":"The role of \u03b2 amyloid in Alzheimer\u2019s disease: Still a cause of everything or the only one who got caught?","volume":"50","author":"Verdile","year":"2004","journal-title":"Pharmacol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1002\/1531-8249(199912)46:6<860::AID-ANA8>3.0.CO;2-M","article-title":"Soluble pool of A\u03b2 amyloid as a determinant of severity of neurodegeneration in Alzheimer\u2019s disease","volume":"46","author":"McLean","year":"1999","journal-title":"Ann. Neurol."},{"key":"ref_19","first-page":"123","article-title":"Automated identification and quantitative morphometry of the senile plaques of Alzheimer\u2019s disease","volume":"19","author":"Hibbard","year":"1997","journal-title":"Anal. Quant. Cytol. Histol. Int. Acad. Cytol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1212\/WNL.38.11.1682","article-title":"Clinico-pathologic studies in dementia Nondemented subjects with pathologically confirmed Alzheimer\u2019s disease","volume":"38","author":"Crystal","year":"1988","journal-title":"Neurology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1523\/JNEUROSCI.22-05-01858.2002","article-title":"The relationship between A\u03b2 and memory in the Tg2576 mouse model of Alzheimer\u2019s disease","volume":"22","author":"Westerman","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1006\/exnr.1995.1080","article-title":"Clusterin (apoJ) alters the aggregation of amyloid \u03b2-peptide (A \u03b21\u201342) and forms slowly sedimenting A \u03b2 complexes that cause oxidative stress","volume":"136","author":"Oda","year":"1995","journal-title":"Exp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/S0002-9440(10)65184-X","article-title":"Soluble amyloid \u03b2 peptide concentration as a predictor of synaptic change in Alzheimer\u2019s disease","volume":"155","author":"Lue","year":"1999","journal-title":"Am. J. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/nm1782","article-title":"Amyloid-\u03b2 protein dimers isolated directly from Alzheimer\u2019s brains impair synaptic plasticity and memory","volume":"14","author":"Shankar","year":"2008","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.1073\/pnas.95.11.6448","article-title":"Diffusible, nonfibrillar ligands derived from A\u03b21\u201342 are potent central nervous system neurotoxins","volume":"95","author":"Lambert","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10191","DOI":"10.1523\/JNEUROSCI.3432-04.2004","article-title":"Synaptic targeting by Alzheimer\u2019s-related amyloid \u03b2 oligomers","volume":"24","author":"Lacor","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.1523\/JNEUROSCI.1633-03.2004","article-title":"Block of long-term potentiation by naturally secreted and synthetic amyloid-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-Terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as M","volume":"24","author":"Wang","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1523\/JNEUROSCI.4391-04.2005","article-title":"Certain inhibitors of synthetic amyloid \u03b2-peptide (A\u03b2) fibrillogenesis block oligomerization of natural A\u03b2 and thereby rescue long-term potentiation","volume":"25","author":"Walsh","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.pneurobio.2009.01.001","article-title":"Inflammation in Alzheimer\u2019s disease: Amyloid-B oligomers trigger innate immunity defence via pattern recognition receptors","volume":"87","author":"Salminen","year":"2009","journal-title":"Prog. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/nrn3880","article-title":"Immune attack: The role of inflammation in Alzheimer disease","volume":"16","author":"Heppner","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1159\/000110455","article-title":"Cellular physiology and biochemistr y biochemistry role of the Toll-Like receptor 4 in Neuro- inflammation in Alzheimer\u2019s disease","volume":"20","author":"Walter","year":"2007","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nature04533","article-title":"A specific amyloid-\u03b2 protein assembly in the brain impairs memory","volume":"440","author":"Koh","year":"2006","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"597","DOI":"10.2174\/156802606776743066","article-title":"The role of amyloid-\u03b2 derived diffusible ligands (ADDLs) in Alzheimer\u2019s disease","volume":"6","author":"Catalano","year":"2006","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/416535a","article-title":"Naturally secreted oligomers of amyloid \u03b2 protein potently inhibit hippocampal long-term potentiation in vivo","volume":"416","author":"Walsh","year":"2002","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/nm1234","article-title":"Amyloid \u03b2 protein immunotherapy neutralizes A\u03b2 oligomers that disrupt synaptic plasticity in vivo","volume":"11","author":"Klyubin","year":"2005","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1126\/science.1079469","article-title":"Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis","volume":"300","author":"Kayed","year":"2003","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1016\/j.neurobiolaging.2009.11.007","article-title":"Cognitive effects of cell-derived and synthetically derived A\u03b2 oligomers","volume":"32","author":"Reed","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1136\/jnnp.66.2.137","article-title":"The cholinergic hypothesis of Alzheimer\u2019s disease: A review of progress","volume":"66","author":"Francis","year":"1999","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/ni.3102","article-title":"Innate immunity in Alzheimer\u2019s disease","volume":"16","author":"Heneka","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.neuroscience.2004.07.036","article-title":"Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the \u03b2-amyloid peptide intracellularly in hippocampal and cortical neurons","volume":"129","author":"Echeverria","year":"2004","journal-title":"Neuroscience"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3233\/JAD-2010-1349","article-title":"A novel transgenic rat model with a full Alzheimer\u2019s-like amyloid pathology displays pre-plaque intracellular amyloid-\u03b2-associated cognitive impairment","volume":"20","author":"Leon","year":"2010","journal-title":"J. Alzheimer Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0165-0173(01)00067-4","article-title":"Applications of the MORRIS water maze in the study of learning and memory","volume":"36","year":"2001","journal-title":"Brain Res. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1111\/bpa.12199","article-title":"Age-dependent effect of \u03b2-amyloid toxicity on basal forebrain cholinergic neurons and inflammation in the rat brain","volume":"25","author":"Nell","year":"2015","journal-title":"Brain Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0014-2999(03)01272-X","article-title":"The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review","volume":"463","author":"Prut","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.bbrc.2007.04.195","article-title":"A transgenic rat expressing human APP with the Swedish Alzheimer\u2019s disease mutation","volume":"358","author":"Folkesson","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1111\/j.1582-4934.2009.00809.x","article-title":"Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer\u2019s disease","volume":"14","author":"Kloskowska","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13629","DOI":"10.1523\/JNEUROSCI.1353-14.2014","article-title":"Alzheimer\u2019s disease-like pathology induced by amyloid-oligomers in nonhuman primates","volume":"34","author":"Batista","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","article-title":"Phases of A \u03b2-deposition in the human brain and its relevance for the development of AD","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1523\/JNEUROSCI.21-02-00372.2001","article-title":"Age-dependent changes in brain, CSF, and plasma amyloid \u03b2 protein in the Tg2576 transgenic mouse model of Alzheimer\u2019s disease","volume":"21","author":"Kawarabayashi","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1471-4159.2011.07478.x","article-title":"Soluble A\u03b2 oligomer production and toxicity","volume":"120","author":"Larson","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_51","first-page":"950783","article-title":"Breaking the code of amyloid-\u03b2 oligomers","volume":"2013","year":"2013","journal-title":"Int. J. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1742-2094-6-1","article-title":"Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia","volume":"6","author":"Sondag","year":"2009","journal-title":"J. Neuroinflamm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.2353\/ajpath.2009.090418","article-title":"Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid \u03b2 neurotoxicity in in vitro and in vivo models of Alzheimer\u2019s disease","volume":"175","author":"Doi","year":"2009","journal-title":"Am. J. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/9\/1390\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:29:06Z","timestamp":1760210946000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/9\/1390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,24]]},"references-count":53,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2016,9]]}},"alternative-id":["ijms17091390"],"URL":"https:\/\/doi.org\/10.3390\/ijms17091390","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,24]]}}}