{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:46:54Z","timestamp":1790059614705,"version":"4.0.1"},"reference-count":73,"publisher":"American Society for Cell Biology (ASCB)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2015,3,15]]},"abstract":"<jats:p> Disruption of fast axonal transport (FAT) and intracellular Ca<jats:sup>2+<\/jats:sup> dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-\u03b2 oligomers (A\u03b2Os), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca<jats:sup>2+<\/jats:sup>-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal A\u03b2O binding sites are unknown. Here we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca<jats:sup>2+<\/jats:sup> elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of A\u03b2Os despite compelling reports of presynaptic A\u03b2Os in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca<jats:sup>2+<\/jats:sup> influx through axonal voltage-gated Ca<jats:sup>2+<\/jats:sup> channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca<jats:sup>2+<\/jats:sup> release from the ER. This work establishes a novel role for Ca<jats:sup>2+<\/jats:sup> dysregulation in BDNF transport disruption and tau-independent A\u03b2 toxicity in early AD. <\/jats:p>","DOI":"10.1091\/mbc.e14-12-1612","type":"journal-article","created":{"date-parts":[[2015,1,22]],"date-time":"2015-01-22T05:51:48Z","timestamp":1421905908000},"page":"1058-1071","source":"Crossref","is-referenced-by-count":38,"title":["Dendritic and axonal mechanisms of Ca<sup>2+<\/sup> elevation impair BDNF transport in A\u03b2 oligomer\u2013treated hippocampal neurons"],"prefix":"10.1091","volume":"26","author":[{"given":"Kathlyn J.","family":"Gan","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Biochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Silverman","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry and"},{"name":"Department of Biological Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada"},{"name":"Brain Research Centre, University of British Columbia, Vancouver, BC V6T 2B5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1076","reference":[{"key":"B70","doi-asserted-by":"crossref","first-page":"2887","DOI":"10.1016\/S0006-3495(99)77120-1","volume":"77","author":"Abney JR","year":"1999","journal-title":"Biophys J"},{"key":"B1","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1016\/j.bbadis.2011.08.013","volume":"1812","author":"Anekonda TS","year":"2011","journal-title":"Biochim Biophys Acta"},{"key":"B2","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00424-009-0736-1","volume":"459","author":"Berridge MJ","year":"2010","journal-title":"Pflugers Arch"},{"key":"B3","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3233\/JAD-2004-6305","volume":"6","author":"Bobich JA","year":"2004","journal-title":"J Alzheimers Dis"},{"key":"B72","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.1073\/pnas.1322170111","volume":"111","author":"Bulgari D","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B4","doi-asserted-by":"crossref","first-page":"10048","DOI":"10.1523\/JNEUROSCI.0217-13.2013","volume":"33","author":"Cantuti Castelvetri L","year":"2013","journal-title":"J Neurosci"},{"key":"B5","doi-asserted-by":"crossref","first-page":"276","DOI":"10.2174\/1570159X11311030004","volume":"11","author":"Cataldi M","year":"2013","journal-title":"Curr Neuropharmacol"},{"key":"B6","doi-asserted-by":"crossref","first-page":"e52056","DOI":"10.1371\/journal.pone.0052056","volume":"7","author":"Chakroborty S","year":"2012","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1007\/s11427-011-4205-7","volume":"54","author":"Chakroborty S","year":"2011","journal-title":"Sci China Life Sci"},{"key":"B8","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.brainresbull.2013.12.004","volume":"103","author":"Cochran JN","year":"2013","journal-title":"Brain Res Bull"},{"key":"B9","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1242\/dmm.006841","volume":"4","author":"Copenhaver PF","year":"2011","journal-title":"Dis Model Mech"},{"key":"B10","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1111\/j.1471-4159.2010.07058.x","volume":"115","author":"Decker H","year":"2010","journal-title":"J Neurochem"},{"key":"B11","doi-asserted-by":"crossref","first-page":"9166","DOI":"10.1523\/JNEUROSCI.1074-10.2010","volume":"30","author":"Decker H","year":"2010","journal-title":"J Neurosci"},{"key":"B12","doi-asserted-by":"crossref","first-page":"11590","DOI":"10.1074\/jbc.M607483200","volume":"282","author":"De Felice FG","year":"2007","journal-title":"J Biol Chem"},{"key":"B13","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1016\/j.neurobiolaging.2007.02.029","volume":"29","author":"De Felice FG","year":"2008","journal-title":"Neurobiol Aging"},{"key":"B14","doi-asserted-by":"crossref","first-page":"12463","DOI":"10.1074\/jbc.R109.080895","volume":"285","author":"Demuro A","year":"2010","journal-title":"J Biol Chem"},{"key":"B15","doi-asserted-by":"crossref","first-page":"30236","DOI":"10.1074\/jbc.M113.480079","volume":"288","author":"Deng M","year":"2013","journal-title":"J Biol Chem"},{"key":"B16","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1093\/hmg\/ddt505","volume":"23","author":"Dolma K","year":"2014","journal-title":"Hum Mol Genet"},{"key":"B17","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nrn3311","volume":"13","author":"Dolphin AC","year":"2012","journal-title":"Nat Rev Neurosci"},{"key":"B18","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.nlm.2011.08.003","volume":"96","author":"Ferreira ST","year":"2011","journal-title":"Neurobiol Learn Mem"},{"key":"B19","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1080\/15216540701283882","volume":"59","author":"Ferreira ST","year":"2007","journal-title":"IUBMB Life"},{"key":"B20","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.pneurobio.2012.03.006","volume":"99","author":"Goldstein LS","year":"2012","journal-title":"Prog Neurobiol"},{"key":"B21","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1083\/jcb.123.4.949","volume":"123","author":"Hell JW","year":"1993","journal-title":"J Cell Biol"},{"key":"B22","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ejphar.2013.01.030","volume":"702","author":"Hermann D","year":"2013","journal-title":"Eur J Pharmacol"},{"key":"B23","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1111\/j.1471-4159.2007.05194.x","volume":"104","author":"Hooper C","year":"2008","journal-title":"J Neurochem"},{"key":"B24","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/nrn2967","volume":"12","author":"Ittner LM","year":"2011","journal-title":"Nat Rev Neurosci"},{"key":"B68","doi-asserted-by":"crossref","first-page":"5819","DOI":"10.1073\/pnas.1017033108","volume":"108","author":"Jin M","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B25","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.1038\/nprot.2006.356","volume":"1","author":"Kaech S","year":"2006","journal-title":"Nat Protoc"},{"key":"B26","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.cell.2010.02.042","volume":"141","author":"Kennedy MJ","year":"2010","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1534\/genetics.113.151639","volume":"195","author":"Kern JV","year":"2013","journal-title":"Genetics"},{"key":"B28","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.brainres.2004.10.041","volume":"1031","author":"Kokubo H","year":"2005","journal-title":"Brain Res"},{"key":"B29","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.neurobiolaging.2004.04.008","volume":"26","author":"Kokubo H","year":"2005","journal-title":"Neurobiol Aging"},{"key":"B30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s12035-009-8050-7","volume":"39","author":"Kuczewski N","year":"2009","journal-title":"Mol Neurobiol"},{"key":"B31","first-page":"1144","volume":"27","author":"Kwinter D","year":"2009","journal-title":"J Vis Exp"},{"key":"B32","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.1073\/pnas.95.11.6448","volume":"95","author":"Lambert MP","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"B33","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/j.1471-4159.2006.04157.x","volume":"100","author":"Lambert MP","year":"2007","journal-title":"J Neurochem"},{"key":"B34","doi-asserted-by":"crossref","first-page":"7011","DOI":"10.1523\/JNEUROSCI.4272-06.2007","volume":"27","author":"Lazarov O","year":"2007","journal-title":"J Neurosci"},{"key":"B35","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1074\/jbc.M211152200","volume":"278","author":"Lee JR","year":"2003","journal-title":"J Biol Chem"},{"key":"B36","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.neuroscience.2009.08.006","volume":"164","author":"Leitch B","year":"2009","journal-title":"Neuroscience"},{"key":"B37","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.neulet.2011.01.018","volume":"491","author":"Lo KY","year":"2011","journal-title":"Neurosci Lett"},{"key":"B38","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/nrn3505","volume":"14","author":"Lu B","year":"2013","journal-title":"Nat Rev Neurosci"},{"key":"B39","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/tra.12142","volume":"15","author":"Maeder CI","year":"2014","journal-title":"Traffic"},{"key":"B40","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/j.bbrc.2003.10.046","volume":"311","author":"Mansuy IM","year":"2003","journal-title":"Biochem Biophys Res Commun"},{"key":"B41","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nrn3380","volume":"14","author":"Millecamps S","year":"2013","journal-title":"Nat Rev Neurosci"},{"issue":"1","key":"B42","doi-asserted-by":"crossref","first-page":"S89","DOI":"10.1007\/s00259-007-0707-8","volume":"35","author":"Minoshima S","year":"2008","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B67","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1111\/j.1474-9726.2012.00816.x","volume":"11","author":"Miranda CJ","year":"2012","journal-title":"Aging Cell"},{"key":"B43","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/emboj\/21.3.281","volume":"21","author":"Morfini G","year":"2002","journal-title":"EMBO J"},{"key":"B44","doi-asserted-by":"crossref","first-page":"11618","DOI":"10.1523\/JNEUROSCI.0012-13.2013","volume":"33","author":"Orefice LL","year":"2013","journal-title":"J Neurosci"},{"key":"B45","doi-asserted-by":"crossref","first-page":"11820","DOI":"10.1523\/JNEUROSCI.0875-12.2012","volume":"32","author":"Oules B","year":"2012","journal-title":"J Neurosci"},{"key":"B73","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1038\/nprot.2006.172","volume":"1","author":"Palmer AE","year":"2006","journal-title":"Nat Protoc"},{"key":"B46","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1089\/ars.2010.3287","volume":"14","author":"Paula-Lima AC","year":"2011","journal-title":"Antioxid Redox Signal"},{"key":"B47","doi-asserted-by":"crossref","first-page":"4499","DOI":"10.1523\/JNEUROSCI.23-11-04499.2003","volume":"23","author":"Pigino G","year":"2003","journal-title":"J Neurosci"},{"key":"B48","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1756-6606-2-33","volume":"2","author":"Pineda JR","year":"2009","journal-title":"Mol Brain"},{"key":"B49","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/S0006-8993(02)03547-3","volume":"956","author":"Ramsden M","year":"2002","journal-title":"Brain Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e12-12-0858"},{"key":"B51","doi-asserted-by":"crossref","first-page":"685","DOI":"10.2174\/157015911798376316","volume":"9","author":"Reese LC","year":"2011","journal-title":"Curr Neuropharmacol"},{"key":"B52","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.neuroscience.2012.10.014","volume":"239","author":"Rothman SM","year":"2013","journal-title":"Neuroscience"},{"key":"B53","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/0167-5699(92)90111-J","volume":"13","author":"Schreiber SL","year":"1992","journal-title":"Immunol Today"},{"key":"B54","doi-asserted-by":"crossref","first-page":"e1003792","DOI":"10.1371\/journal.pgen.1003792","volume":"9","author":"Shaw JL","year":"2013","journal-title":"PLoS Genet"},{"key":"B55","doi-asserted-by":"crossref","first-page":"11998","DOI":"10.1073\/pnas.0802175105","volume":"105","author":"Shimizu H","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"B56","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1002\/mrm.22733","volume":"65","author":"Smith KD","year":"2011","journal-title":"Magn Reson Med"},{"key":"B57","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1093\/hmg\/ddn240","volume":"17","author":"Stokin GB","year":"2008","journal-title":"Hum Mol Genet"},{"key":"B58","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1196\/annals.1379.025","volume":"1097","author":"Stutzmann GE","year":"2007","journal-title":"Ann NY Acad Sci"},{"key":"B71","doi-asserted-by":"crossref","first-page":"R623","DOI":"10.1016\/j.cub.2013.06.005","volume":"23","author":"Trybus KM","year":"2013","journal-title":"Curr Biol"},{"key":"B59","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1126\/science.1194653","volume":"330","author":"Vossel KA","year":"2010","journal-title":"Science"},{"key":"B60","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.cell.2008.11.046","volume":"136","author":"Wang X","year":"2009","journal-title":"Cell"},{"key":"B61","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/tra.12037","volume":"14","author":"Weaver C","year":"2013","journal-title":"Traffic"},{"key":"B69","doi-asserted-by":"crossref","first-page":"3908","DOI":"10.1021\/bi5003053","volume":"53","author":"Welzel AT","year":"2014","journal-title":"Biochemistry"},{"key":"B62","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1007\/s12031-008-9080-8","volume":"37","author":"Wong MY","year":"2009","journal-title":"J Mol Neurosci"},{"key":"B63","doi-asserted-by":"crossref","first-page":"5298","DOI":"10.1523\/JNEUROSCI.0227-12.2012","volume":"32","author":"Wu HY","year":"2012","journal-title":"J Neurosci"},{"key":"B64","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.neuron.2011.02.049","volume":"70","author":"Yin X","year":"2011","journal-title":"Neuron"},{"key":"B65","doi-asserted-by":"crossref","first-page":"8472","DOI":"10.1523\/JNEUROSCI.4585-12.2013","volume":"33","author":"Yoshii A","year":"2013","journal-title":"J Neurosci"},{"key":"B66","doi-asserted-by":"crossref","first-page":"11938","DOI":"10.1523\/JNEUROSCI.2357-10.2010","volume":"30","author":"Zempel H","year":"2010","journal-title":"J Neurosci"}],"container-title":["Molecular Biology of the Cell"],"original-title":[],"language":"en","deposited":{"date-parts":[[2019,7,14]],"date-time":"2019-07-14T16:34:31Z","timestamp":1563122071000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.molbiolcell.org\/doi\/10.1091\/mbc.E14-12-1612"}},"subtitle":[],"editor":[{"given":"Erika","family":"Holzbaur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,3,15]]},"references-count":73,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2015,3,15]]}},"alternative-id":["10.1091\/mbc.E14-12-1612"],"URL":"https:\/\/doi.org\/10.1091\/mbc.e14-12-1612","relation":{},"ISSN":["1059-1524","1939-4586"],"issn-type":[{"value":"1059-1524","type":"print"},{"value":"1939-4586","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,15]]}}}