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We found that patients with the V97L mutation had increased levels of extracellular and intracellular A\u03b242. Here we found that the increased extracellular level of A\u03b242 was always accompanied by a reduction of insulin\u2010degrading enzyme (IDE) activity on the plasma membranes. However, increase of intracellular A\u03b242 was associated with decreased expression and activity of IDE in the cytosol and endoplasmic reticulum in the PS1\u2003V97L mutant\u2010transfected human SH\u2010SY5Y cell line. These studies indicate that pathological levels of A\u03b242 may be caused by the negative effects of PS1 (V97L) on IDE expression and activity. Our findings provide evidence for the molecular basis of familial Alzheimer's disease pathogenesis.<\/jats:p>","DOI":"10.1111\/j.1460-9568.2008.06207.x","type":"journal-article","created":{"date-parts":[[2008,4,25]],"date-time":"2008-04-25T08:40:37Z","timestamp":1209112837000},"page":"2425-2432","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Down\u2010regulation of insulin\u2010degrading enzyme by presenilin\u20031\u2003V97L mutant potentially underlies increased levels of amyloid beta\u200342"],"prefix":"10.1111","volume":"27","author":[{"given":"Wei","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,4,25]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401030101"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600251"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh077"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5500.2302"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-002-0459-2"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.00855.x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0997-1021"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63822-9"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3133-06.2006"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/156720507780362245"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.07.017"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200642200"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2006.06.072"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19980601)52:5<618::AID-JNR14>3.0.CO;2-Y"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/72215"},{"key":"e_1_2_7_17_1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3233\/JAD-2007-11109","article-title":"Ultrastructural localization of intraneuronal Abeta\u2010peptide in Alzheimer disease brains","volume":"11","author":"G\u00f3mez\u2010Ramos P.","year":"2007","journal-title":"J. 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