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Monoclonal antibodies (mAbs) that target A\u03b2 for clearance from the brain are FDA-approved; however, these therapies are associated with serious side effects, and their cognitive benefit remains debated. We present a potential engineered therapy for AD in which we enlist cells of the central nervous system as programmable agents for sculpting the neurodegenerative niche to mitigate glial reactivity and neuronal loss. We constructed a suite of A\u03b2-sensitive synthetic Notch (synNotch) receptors from anti-A\u03b2 mAbs and show that cells expressing them can recognize distinct A\u03b2 species with differential sensitivity. We validate A\u03b2-synNotch receptor activity in microglia and astrocytes, cells native to the brain that become dysfunctional in AD. SynNotch astrocytes engineered to express antagonists of the pro-inflammatory cytokines TNF and IL-1 resist a cytokine-induced, reactive phenotype. Finally, A\u03b2-synNotch cells potently upregulate transgene expression in response to A\u03b2 deposits in 5xFAD mouse brains. We also adapt the A\u03b2 receptor for a gene therapy, supporting a translational strategy that bypasses the need for\n                  <jats:italic>ex vivo<\/jats:italic>\n                  cell engineering. Together, these results establish A\u03b2-responsive synthetic receptors for conditional delivery of disease-modifying factors to the AD microenvironment.\n                <\/jats:p>","DOI":"10.1101\/2025.03.12.642808","type":"posted-content","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T15:41:19Z","timestamp":1742398879000},"source":"Crossref","is-referenced-by-count":3,"title":["Amyloid-\u03b2-regulated gene circuits for programmable Alzheimer\u2019s disease therapy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1172-4771","authenticated-orcid":false,"given":"Madeline R.","family":"Spetz","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyosung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, 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