{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:18:02Z","timestamp":1790511482865,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,9,18]],"date-time":"2013-09-18T00:00:00Z","timestamp":1379462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Alzheimer's disease (<jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content>) is a neurodegenerative disorder characterized by pathological deposits of \u03b2\u2010amyloid (<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>\u03b2) in senile plaques, intracellular neurofibrillary tangles (<jats:styled-content style=\"fixed-case\">NFT<\/jats:styled-content>s) comprising hyperphosphorylated aggregated tau, synaptic dysfunction and neuronal death. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content> that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (<jats:styled-content style=\"fixed-case\">NCX<\/jats:styled-content>s) play important roles in regulating intracellular calcium, and accumulating data suggests that reduced <jats:styled-content style=\"fixed-case\">NCX<\/jats:styled-content> function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. Here, we show that elevated calpain, but not caspase\u20103, activity is a prominent feature of <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content> brain. In addition, we observe increased calpain\u2010mediated cleavage of <jats:styled-content style=\"fixed-case\">NCX<\/jats:styled-content>3, but not a related family member <jats:styled-content style=\"fixed-case\">NCX<\/jats:styled-content>1, in <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content> brain relative to unaffected tissue and that from other neurodegenerative conditions. Moreover, the extent of <jats:styled-content style=\"fixed-case\">NCX<\/jats:styled-content>3 proteolysis correlated significantly with amounts of <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>\u03b21\u201342. We also show that exposure of primary cortical neurons to oligomeric <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>\u03b21\u201342 results in calpain\u2010dependent cleavage of <jats:styled-content style=\"fixed-case\">NCX<\/jats:styled-content>3, and we demonstrate that loss of <jats:styled-content style=\"fixed-case\">NCX<\/jats:styled-content>3 function is associated with <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>\u03b2 toxicity. Our findings suggest that <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>\u03b2 mediates calpain cleavage of <jats:styled-content style=\"fixed-case\">NCX<\/jats:styled-content>3 in <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content> brain and therefore that reduced <jats:styled-content style=\"fixed-case\">NCX<\/jats:styled-content>3 activity could contribute to the sustained increases in intraneuronal calcium concentrations that are associated with synaptic and neuronal dysfunction in <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/acel.12148","type":"journal-article","created":{"date-parts":[[2013,8,7]],"date-time":"2013-08-07T02:12:59Z","timestamp":1375841579000},"page":"49-59","source":"Crossref","is-referenced-by-count":45,"title":["Calpain cleavage and inactivation of the sodium calcium exchanger\u20103 occur downstream of <scp>A<\/scp>\u03b2 in <scp>A<\/scp>lzheimer's disease"],"prefix":"10.1111","volume":"13","author":[{"given":"Joe","family":"Atherton","sequence":"first","affiliation":[{"name":"Institute of Psychiatry Department of Neuroscience King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ksenia","family":"Kurbatskaya","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry Department of Neuroscience King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Bondulich","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry Department of Neuroscience King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara L.","family":"Croft","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry Department of Neuroscience King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire J.","family":"Garwood","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry Department of Neuroscience King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Resham","family":"Chhabra","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry Department of Neuroscience King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selina","family":"Wray","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry Department of Neuroscience King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Jeromin","sequence":"additional","affiliation":[{"name":"NextGenSciences Dx 155 Federal Street Suite 700 Boston MA 02110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane P.","family":"Hanger","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry Department of Neuroscience King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Noble","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry Department of Neuroscience King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,9,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.22.10573"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2006.04.041"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.11.049"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1387.006"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22295"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410270502"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2011.50"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2002"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702793200"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.024190"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.028464"},{"key":"e_1_2_7_13_1","first-page":"95","article-title":"Mechanisms of cell death in neurodegenerative disorders","volume":"59","author":"Jellinger KA","year":"2000","journal-title":"J. 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