{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T02:21:40Z","timestamp":1785464500846,"version":"3.56.0"},"reference-count":64,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T00:00:00Z","timestamp":1686182400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The decades\u2010old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the \u03b17 nicotinic acetylcholine receptor (\u03b17nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid \u03b2<jats:sub>1\u201042<\/jats:sub> (A\u03b2<jats:sub>42<\/jats:sub>) was shown to bind \u03b17nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau\u2010containing tangles. Multiple biopharmaceutical companies explored \u03b17nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting \u03b17nAChR proved to be a drug development challenge. The ultra\u2010high\u2010affinity interaction between A\u03b2<jats:sub>42<\/jats:sub> and \u03b17nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of \u03b17nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug\u2010related toxicities. As alternatives, proteins interacting with \u03b17nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with \u03b17nAChR was shown to be critical to A\u03b2<jats:sub>42<\/jats:sub>'s toxic signaling via \u03b17nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A\u2013\u03b17nAChR interaction, reduces A\u03b2<jats:sub>42<\/jats:sub>'s high\u2010affinity binding to \u03b17nAChR, and suppresses A\u03b2<jats:sub>42<\/jats:sub>'s toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease\u2010modifying treatment for AD.<\/jats:p>","DOI":"10.1002\/ddr.22085","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T01:59:35Z","timestamp":1686275975000},"page":"1085-1095","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Targeting \u03b17 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development"],"prefix":"10.1002","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-3174","authenticated-orcid":false,"given":"Lindsay H.","family":"Burns","sequence":"first","affiliation":[{"name":"Cassava Sciences, Inc. Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular and Biomedical Sciences City University of New York School of Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoau\u2010Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular and Biomedical Sciences City University of New York School of Medicine New York New York USA"},{"name":"Department of Biology and Neuroscience Graduate School of the City University of New York New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,8]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-020-00599-1"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.12.5562"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.1038343"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2016.06.013"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.2002.1112"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.113.008581"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301189"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.02.025"},{"key":"e_1_2_12_10_1","volume-title":"The use of morphine and scopolamine to induce twilight sleep","author":"Cartwright J.","year":"2019"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161206775474224"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2559.2001.01082.x"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1586\/14737175.2015.995639"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi201246t"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M200066200"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.110.173245"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6159-08.2009"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2007.01.045"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13001"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2008.07071135"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-016-0210-1"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2015.06.001"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881117691590"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.01.018"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2016.101"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0953-816X.2004.03377.x"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.5038-09.2010"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2009.05.665"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-020-0628-9"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-4328(00)00211-4"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.7b00032"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108025"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07761"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2018.12.003"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.151886"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.04.008"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm301048a"},{"key":"e_1_2_12_38_1","unstructured":"Memory Pharmaceuticals. (2007). Memory pharmaceuticals announces positive phase 2a results for MEM 3454 in Alzheimer's disease [press release]."},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00460-2"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.283.12.1571"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0701321104"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(86)90629-4"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.pra.0000442935.15833.c5"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0173(88)90016-1"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490270314"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2009.07.005"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.01.033"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-3458.2008.00037.x"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.120436"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26569"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2014.17"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-014-0201-3"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbv072"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0354-12.2012"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2009.09.031"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.8.5626"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0751155.x"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2017.03.016"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212532200"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2020.6"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.119.263483"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(86)90819-x"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2017.09.001"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0804372105"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay0289"}],"container-title":["Drug Development Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.22085","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T21:18:25Z","timestamp":1760390305000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/ddr.22085"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,8]]},"references-count":64,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1002\/ddr.22085"],"URL":"https:\/\/doi.org\/10.1002\/ddr.22085","archive":["Portico"],"relation":{},"ISSN":["0272-4391","1098-2299"],"issn-type":[{"value":"0272-4391","type":"print"},{"value":"1098-2299","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,8]]},"assertion":[{"value":"2023-03-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}