{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:42:50Z","timestamp":1791592970970,"version":"4.3.4"},"reference-count":57,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The rising prevalence of Alzheimer's disease (AD) highlights the urgent need for novel therapeutic approaches capable of suppressing further neurodegeneration. Aberrant aggregation of the amyloid-\u03b2 peptide fragment of the amyloid-\u03b2 protein precursor (APP) has long been considered to be a central feature of AD pathology. However, directly targeting the amyloid-\u03b2 peptide is complicated by its conformational flexibility. Instead, reducing APP expression at the translational level represents a promising alternative. The highly structured 5\u2032 untranslated region (UTR) of APP mRNA provides a targetable element for selective inhibition using RNA-binding therapeutics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To develop and evaluate engineered protein-based RNA binders (PROTEIMERs) that selectively target the APP 5\u2032-UTR to inhibit translation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We applied high-throughput phage display screening techniques to identify two PROTEIMERs with high affinity for the APP 5\u2032-UTR, confirmed via surface plasmon resonance. Domain engineering enabled the fusion of these binders to an RNase domain to facilitate catalytic degradation of APP mRNA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PROTEIMERs bound the APP 5\u2032-UTR with nanomolar affinity. Structural modeling of the PROTEIMER\u2013RNA complexes revealed that the engineered mutations within the binding pocket predominantly interact with the 5\u2032-AGA-3\u2032 cleft of the APP mRNA. RNase-fused PROTEIMERs mediated sequence-specific APP mRNA cleavage in vitro, demonstrating robust target engagement and degradation. The PROTEIMER ProAPPS3-11 effectively inhibited APP translation in SH-SY5Y cells, reducing protein levels by up to 60% in a dose-dependent manner.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings establish the feasibility of PROTEIMERs as novel RNA-targeting biologics with therapeutic potential to reduce APP mRNA and protein levels, mitigating downstream AD-related neurodegeneration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251393907","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:08:09Z","timestamp":1763575689000},"page":"303-314","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["PROTEIMERs as catalytic inhibitors of APP mRNA translation: Toward a new therapeutic for Alzheimer's disease"],"prefix":"10.1177","volume":"109","author":[{"given":"Daniel","family":"von Salzen","sequence":"first","affiliation":[{"name":"CrossLife Technologies Inc., Carlsbad, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Senn","sequence":"additional","affiliation":[{"name":"CrossLife Technologies Inc., Carlsbad, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah K","family":"Cho","sequence":"additional","affiliation":[{"name":"CrossLife Technologies Inc., Carlsbad, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine M","family":"Cahill","sequence":"additional","affiliation":[{"name":"Neurochemistry Laboratory, Massachusetts General Hospital (East), and Harvard Medical School, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack T","family":"Rogers","sequence":"additional","affiliation":[{"name":"Neurochemistry Laboratory, Massachusetts 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