{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:48:05Z","timestamp":1792723685572,"version":"4.5.0"},"reference-count":27,"publisher":"National Academy of Sciences","issue":"47","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,11,21]]},"abstract":"<jats:p>\n                    Rare familial forms of Alzheimer's disease (AD) are thought to be caused by elevated proteolytic production of the A\u03b242 peptide from the \u03b2-amyloid-precursor protein (APP). Although the pathogenesis of the more common late-onset AD (LOAD) is not understood, BACE1, the protease that cleaves APP to generate the N terminus of A\u03b242, is more active in patients with LOAD, suggesting that increased amyloid production processing might also contribute to the sporadic disease. Using high-throughput siRNA screening technology, we assessed 15,200 genes for their role in A\u03b242 secretion and identified leucine-rich repeat transmembrane 3 (\n                    <jats:italic>LRRTM3<\/jats:italic>\n                    ) as a neuronal gene that promotes APP processing by BACE1. siRNAs targeting\n                    <jats:italic>LRRTM3<\/jats:italic>\n                    inhibit the secretion of A\u03b240, A\u03b242, and sAPP\u03b2, the N-terminal APP fragment produced by BACE1 cleavage, from cultured cells and primary neurons by up to 60%, whereas overexpression increases A\u03b2 secretion. LRRTM3 is expressed nearly exclusively in the nervous system, including regions affected during AD, such as the dentate gyrus. Furthermore,\n                    <jats:italic>LRRTM3<\/jats:italic>\n                    maps to a region of chromosome 10 linked to both LOAD and elevated plasma A\u03b242, and is structurally similar to a family of neuronal receptors that includes the NOGO receptor, an inhibitor of neuronal regeneration and APP processing. Thus,\n                    <jats:italic>LRRTM3<\/jats:italic>\n                    is a functional and positional candidate gene for AD, and, given its receptor-like structure and restricted expression, a potential therapeutic target.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0605461103","type":"journal-article","created":{"date-parts":[[2006,11,13]],"date-time":"2006-11-13T20:38:56Z","timestamp":1163450336000},"page":"17967-17972","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":77,"title":["<i>LRRTM3<\/i>\n                    promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease"],"prefix":"10.1073","volume":"103","author":[{"given":"John","family":"Majercak","sequence":"first","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Ray","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Espeseth","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Technology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Ping","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie","family":"Wolffe","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista","family":"Getty","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Marine","sequence":"additional","affiliation":[{"name":"Automated Biotechnology, Merck &amp; Co., Inc., West Point, PA 19486;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Stec","sequence":"additional","affiliation":[{"name":"Automated Biotechnology, Merck &amp; Co., Inc., West Point, PA 19486;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ferrer","sequence":"additional","affiliation":[{"name":"Automated Biotechnology, Merck &amp; Co., Inc., West Point, PA 19486;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berta","family":"Strulovici","sequence":"additional","affiliation":[{"name":"Automated Biotechnology, Merck &amp; Co., Inc., West Point, PA 19486;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Bartz","sequence":"additional","affiliation":[{"name":"Departments of \u00a7Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Gates","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Technology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Xu","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Technology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Huang","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Technology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Shughrue","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julja","family":"Burchard","sequence":"additional","affiliation":[{"name":"Departments of \u00a7Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Colussi","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Pietrak","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Kahana","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Beher","sequence":"additional","affiliation":[{"name":"Department of Alzheimer's Research, Merck Research Laboratories, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Rosahl","sequence":"additional","affiliation":[{"name":"Department of Alzheimer's Research, Merck Research Laboratories, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Shearman","sequence":"additional","affiliation":[{"name":"Department of Alzheimer's Research, Merck Research Laboratories, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Hazuda","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Technology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan B.","family":"Sachs","sequence":"additional","affiliation":[{"name":"Molecular Profiling, Rosetta Inpharmatics LLC, Seattle, WA 98109; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth S.","family":"Koblan","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy R.","family":"Seabrook","sequence":"additional","affiliation":[{"name":"Department of *Alzheimer's Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Stone","sequence":"additional","affiliation":[{"name":"Molecular Profiling, Rosetta Inpharmatics LLC, Seattle, WA 98109; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,11,21]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.3.022502.103022"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5440.735"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb960"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0896-864"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0928-4257(98)80035-1"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1124\/mi.2.6.363"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.59.9.1381"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10208"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)02635-9"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5500.2304"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/498851"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-1809.2001.6550473.x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5500.2303"},{"key":"e_1_3_3_14_2","doi-asserted-by":"crossref","unstructured":"XP Shi K Tugusheva JE Bruce A Lucka E Chen-Dodson B Hu GX Wu E Price RB Register J Lineberger et al. 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