{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T22:20:09Z","timestamp":1780093209289,"version":"3.54.0"},"reference-count":35,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2016,9,12]],"date-time":"2016-09-12T00:00:00Z","timestamp":1473638400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2016,10,18]]},"abstract":"<jats:p>\n                    Alzheimer\u2019s disease (AD) is characterized by neuronal death, neurofibrillary tangles, and senile plaques. Amyloid-beta (A\u03b2) is the major component of plaques and consists of two prominent isoforms, A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    and A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    . As many risk factors for AD are vascular in origin and blood vessel defects in clearing A\u03b2 from the brain are a potential key component of AD pathology, we have focused on the neuron-blood vessel interface, and in particular, the vascular basement membrane, which coats blood vessels and physically separates them from neurons. A prominent component of the vascular basement membrane is the extracellular matrix proteoglycan perlecan. Domain V (DV) is the C-terminal domain and is generated by perlecan proteolysis. DV interacts with the \u03b12 integrin and A\u03b2 is a ligand for both \u03b12\u03b21 and \u03b1v\u03b21. Due to the known interaction of DV with \u03b12\u03b21 and \u03b12\u03b21\u2019s requirement for A\u03b2 deposition and neurotoxicity, we hypothesized that DV and\/or its C-terminal domain, LG3, might alter neurotoxic signaling pathways by directly blocking or otherwise interfering with \u03b12\u03b21 binding by A\u03b2. Our study suggests that \u03b12\u03b21 mediates A\u03b2-induced activation of c-Jun and caspase-3, key components of the neurotoxic pathway, in primary cortical and hippocampal neurons. We further demonstrate that DV and\/or LG3 may therapeutically modulate these \u03b12\u03b21 mediated neurotoxic effects suggesting that they or other \u03b12\u03b21 integrin modulators could represent a novel approach to treat AD. Finally, our results suggest different neurotoxicity susceptibilities between cortical and hippocampal neurons to A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    and A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    as further underscored by differing neuroprotective potencies of LG3 in each cell type.\n                  <\/jats:p>","DOI":"10.3233\/jad-160290","type":"journal-article","created":{"date-parts":[[2016,9,13]],"date-time":"2016-09-13T14:42:15Z","timestamp":1473777735000},"page":"1629-1647","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":15,"title":["Perlecan Domain V Inhibits Amyloid-\u03b2 Induced Activation of the \u03b12\u03b21 Integrin-Mediated Neurotoxic Signaling Cascade"],"prefix":"10.1177","volume":"54","author":[{"given":"Christi L.","family":"Parham","sequence":"first","affiliation":[{"name":"Texas A&amp;M Health Science Center, Department of Molecular and Cellular Biology, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Shaw","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Health Science Center, Department of Molecular and Cellular Biology, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa D.","family":"Auckland","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Health Science Center, Department of Molecular and Cellular Biology, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Kent","family":"Dickeson","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Griswold-Prenner","sequence":"additional","affiliation":[{"name":"Imago Pharmaceuticals, Jackson Hole, WY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Bix","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Health Science Center, Department of Molecular and Cellular Biology, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2016,9,12]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.18.020402.142302"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00475-5"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1021910729963"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2010.01137.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6474172"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0177(199710)210:2<130::AID-AJA6>3.0.CO;2-H"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2004.11.008"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409841200"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801164200"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2011.12.027"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200401150"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.243626"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI46358"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.2174\/138945008783502494"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2005.12.002"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.10.018"},{"key":"e_1_3_2_19_2","first-page":"152","article-title":"Hippocampal neuronal loss in the CA1 and CA3 areas of Alzheimer\u2019s disease patients","volume":"24","author":"Padurariu M","year":"2012","unstructured":"PadurariuM, CiobicaA, MavroudisI, FotiouD, BaloyannisS (2012) Hippocampal neuronal loss in the CA1 and CA3 areas of Alzheimer\u2019s disease patients. Psychiatr Danub 24, 152\u2013158.","journal-title":"Psychiatr Danub"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4091-05.2006"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045257"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.10.018"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107176200"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21909"},{"key":"e_1_3_2_25_2","first-page":"221","article-title":"The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines","volume":"111","author":"Chiarini A","year":"2006","unstructured":"ChiariniA, Dal PraI, WhitfieldJF, ArmatoU (2006) The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines. 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