{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T16:13:22Z","timestamp":1778170402805,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,4]]},"group-title":"Neuroscience","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["RF1 AG068296"],"award-info":[{"award-number":["RF1 AG068296"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["R01 AG081989"],"award-info":[{"award-number":["R01 AG081989"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"name":"American Aging Association AGE Early Career Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Pioneering research is adapting chimeric antigen receptors (CARs) from oncology to Alzheimer\u2019s disease (AD) by targeting amyloid beta (A\u03b2). Newer synthetic receptor systems can go beyond, transforming cells into targeted biological drug factories that can couple A\u03b2 detection to synthesis and secretion of genetically encoded therapeutics. Among candidate systems, T cells Redirected for Universal Cytokine Killing (TRUCK), synthetic Notch (synNotch), and Synthetic Intramembrane Proteolysis Receptors (SNIPR) have shown promise in oncology. Here, we adapt these platforms to AD using a shared A\u03b2-targeting binding domain derived from Aducanumab (Aduhelm), coupled to inducible expression cassettes driving identical transgenes: secreted Metridia luciferase (MetLuc) and a Lecanemab (Leqembi)-based chimeric human-mouse antibody (chLecanemab). To validate these systems\n                  <jats:italic>in vitro<\/jats:italic>\n                  , Jurkat clones expressing each receptor were treated with oligomer-enriched A\u03b2 (A\u03b2O) to model AD, and receptor output was quantified by media MetLuc levels and chLecanemab colocalization with A\u03b2 aggregates. For TRUCK systems, we show the A\u03b2-targeting CAR successfully activated Jurkat cells by flow cytometry. We also show that six Nuclear Factor of Activated T-cells (NFAT) tandem repeat response elements (6xNFAT) paired with either minimal interleukin-2, synthetic TATA box, or minimal cytomegalovirus promoters resulted in functional regulatory regions. Despite this, all TRUCK variants failed to significantly upregulate MetLuc in response to A\u03b2O. In contrast, both synNotch and SNIPR responded robustly to A\u03b2O, with SNIPR outperforming synNotch in both MetLuc and chLecanemab production. These findings establish SNIPR and synNotch as promising platforms for future research on cell-based targeted therapeutic delivery in AD.\n                <\/jats:p>","DOI":"10.64898\/2026.04.29.721717","type":"posted-content","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T18:40:16Z","timestamp":1777920016000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>In vitro<\/i>\n                  comparison of A\u03b2-targeting SNIPR, synNotch, and TRUCK for cell-based drug delivery in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5422-1835","authenticated-orcid":false,"given":"Cynthia J.","family":"Siebrand","sequence":"first","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"},{"name":"USC Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave, Los Angeles, CA, 90191, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7717-6357","authenticated-orcid":false,"given":"Zachary","family":"Mayeri","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Brown","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1324-4875","authenticated-orcid":false,"given":"Julie K.","family":"Andersen","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8513-0207","authenticated-orcid":false,"given":"Chaska 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