{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:19:08Z","timestamp":1790813948909,"version":"4.1.0"},"reference-count":92,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2008,8,18]],"date-time":"2008-08-18T00:00:00Z","timestamp":1219017600000},"content-version":"vor","delay-in-days":199,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2008,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The deficits in Alzheimer disease (AD) stem at least partly from neurotoxic \u03b2\u2010amyloid peptides generated from the amyloid precursor protein (APP). APP may also be cleaved intracellularly at Asp664 to yield a second neurotoxic peptide, C31. Previously, we showed that cleavage of APP at the C\u2010terminus is required for the impairments seen in APP transgenic mice, by comparing elements of the disease in animals modeling AD, with (platelet\u2010derived growth factor B\u2010chain promoter\u2010driven APP transgenic mice; PDAPP) versus without (PDAPP D664A) a functional Asp664 caspase cleavage site. However, the signaling mechanism(s) by which Asp664 contributes to these deficits remains to be elucidated. In this study, we identify a kinase protein, recently shown to bind APP at the C\u2010terminus and to contribute to AD, whose activity is modified in PDAPP mice, but normalized in PDAPP D664A mice. Specifically, we observed a significant increase in nuclear p21\u2010activated kinase (isoforms 1, 2, and or 3; PAK\u20101\/2\/3) activation in hippocampus of 3\u2003month old PDAPP mice compared with non\u2010transgenic littermates, an effect completely prevented in PDAPP D664A mice. In contrast, 13\u2003month old PDAPP mice displayed a significant decrease in PAK\u20101\/2\/3 activity, which was once again absent in PDAPP D664A mice. Similarly, in hippocampus of early and severe AD subjects, there was a progressive and subcellular\u2010specific reduction in active PAK\u20101\/2\/3 compared with normal controls. Interestingly, total PAK\u20101\/2\/3 protein was increased in early AD subjects, but declined in moderate AD and declined further, to significantly below that of control levels, in severe AD. These findings are compatible with previous suggestions that PAK may be involved in the pathophysiology of AD, and demonstrate that both early activation and late inactivation in the murine AD model require the cleavage of APP at Asp664.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2007.05031.x","type":"journal-article","created":{"date-parts":[[2007,10,11]],"date-time":"2007-10-11T20:46:25Z","timestamp":1192135585000},"page":"1065-1080","source":"Crossref","is-referenced-by-count":60,"title":["Signal transduction in Alzheimer disease: p21\u2010activated kinase signaling requires C\u2010terminal cleavage of APP at Asp664"],"prefix":"10.1111","volume":"104","author":[{"given":"Thuy\u2010Vi V.","family":"Nguyen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Galvan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surita","family":"Banwait","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huidong","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junli","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale E.","family":"Bredesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,8,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4827(03)00233-7"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/1675"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-005-5597-y"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-0760(03)00220-6"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00546-8"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M506205200"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1058783"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.1167"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.CR0050014"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309561200"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0887-8994(03)00152-8"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M009316200"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2003.11.016"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.1996.tb00878.x"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1385\/JMN:19:3:295"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2001.281.1.C123"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0531-5565(00)00149-2"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.9.6050"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s007020100016"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-3395com"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.00970.x"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509695103"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1385\/JMN:17:2:137"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001508"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2005.05.022"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026073324672"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.05.003"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.6.3228"},{"key":"e_1_2_7_30_1","first-page":"88","article-title":"Amyloid, dementia and Alzheimer\u2019s disease","volume":"5","author":"Hyman B. T.","year":"1992","journal-title":"Curr. Opin. Neurol. Neurosurg."},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306494200"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/80859"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406701200"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-0106fje"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410530200"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0854.2002.31101.x"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010892200"},{"key":"e_1_2_7_38_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3233\/JAD-2004-6205","article-title":"Perspectives on the amyloid\u2010\u03b2 cascade hypothesis","volume":"6","author":"Lee H. G.","year":"2004","journal-title":"J. Alzheimers Dis."},{"key":"e_1_2_7_39_1","first-page":"163","article-title":"The androgen receptor CAG repeat and serum testosterone in the risk of Alzheimer\u2019s disease in men","volume":"75","author":"Lehmann D. J.","year":"2004","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/74833"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/55.3.B160"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/74656"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2003.02059.x"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2004.01.023"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(03)00464-0"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbrainres.2003.08.018"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212265200"},{"key":"e_1_2_7_48_1","first-page":"175","article-title":"Genetically altered transgenic models of Alzheimer\u2019s disease","volume":"59","author":"Masliah E.","year":"2000","journal-title":"J. Neural Transm. Suppl."},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E05-01-0081"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C500217200"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2006.03.007"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(01)00294-7"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-17-06914.2003"},{"key":"e_1_2_7_54_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.3233\/JAD-2000-23-406","article-title":"Oxygen free radical injury is sufficient to cause some Alzheimer\u2010type molecular abnormalities in human CNS neuronal cells","volume":"2","author":"De La Monte S. M.","year":"2000","journal-title":"J. Alzheimers Dis."},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-11-04050.2000"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.9.4205"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.120571797"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00221-002-1016-x"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0330646"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1385\/NMM:5:3:205"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1385\/ENDO:29:2:233"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5216-05.2006"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M404480200"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0978"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2922"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03530.x"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2004.12.016"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4180-06.2006"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69051820.x"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-09-03376.2002"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105410200"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311145200"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.7570"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199909000-00012"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2199-7-33"},{"key":"e_1_2_7_76_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412607200"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567205043332126"},{"key":"e_1_2_7_78_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-15-05703.2001"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M401399200"},{"key":"e_1_2_7_80_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208672"},{"key":"e_1_2_7_81_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-5839fje"},{"key":"e_1_2_7_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209309"},{"key":"e_1_2_7_83_1","doi-asserted-by":"publisher","DOI":"10.1385\/NMM:6:1:053"},{"key":"e_1_2_7_84_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.19.5647"},{"key":"e_1_2_7_85_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010311200"},{"key":"e_1_2_7_86_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311027200"},{"key":"e_1_2_7_87_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.46.32565"},{"key":"e_1_2_7_88_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.7.3785"},{"key":"e_1_2_7_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2003.07.006"},{"key":"e_1_2_7_90_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1630"},{"key":"e_1_2_7_91_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2001-12-0180"},{"key":"e_1_2_7_92_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0047-6374(01)00342-6"},{"key":"e_1_2_7_93_1","doi-asserted-by":"publisher","DOI":"10.2174\/156720506778249470"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1471-4159.2007.05031.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1471-4159.2007.05031.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T21:38:09Z","timestamp":1695937089000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1471-4159.2007.05031.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,2]]},"references-count":92,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2008,2]]}},"alternative-id":["10.1111\/j.1471-4159.2007.05031.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1471-4159.2007.05031.x","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,2]]}}}