{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:00:11Z","timestamp":1790402411786,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":27,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100007625","name":"Cure Alzheimer's Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007625","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;D Transl Res &amp; Clin Interv"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD) is characterized by early synaptic dysfunction followed by progressive amyloid beta (A\u03b2) accumulation, neuroinflammation, and cognitive decline. We previously identified secreted frizzled\u2010related protein 1 (SFRP1) as a multifactorial contributor to AD pathogenesis and provided initial evidence that its neutralization ameliorates pathological AD\u2010like traits in mice. Here we evaluate the pharmacodynamics, biodistribution, and therapeutic window of an anti\u2010SFRP1 monoclonal antibody (\u03b1\u2010SFRP1) in double transgenic amyloid precursor protein (APP) and presenilin\u20101 (PS1) mice (APP\/PS1).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Pharmacokinetics and target engagement of \u03b1\u2010SFRP1 were assessed in groups of both male and female APP\/PS1 mice using biotinylated or Zirconium\u201089 labeled (\n                      <jats:sup>89<\/jats:sup>\n                      Zr) antibodies, with tissue distribution and \u03b1\u2010SFRP1 levels quantified by in\u2010house enzyme\u2010linked immunosorbent assay (ELISA) or positron emission tomography\/computed tomography (PET\/CT). Therapeutic efficacy was evaluated by administering \u03b1\u2010SFRP1 or the SFRP1 inhibitor WAY\u2010316606 at different stages of disease progression via retro\u2010orbital injection, followed by analysis of AD\u2010like pathology using ELISA and quantitative immunofluorescence assays and statistical analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Using\n                      <jats:sup>89<\/jats:sup>\n                      Zr\u2010labeled antibodies, we show that intravenously administered \u03b1\u2010SFRP1 engages its target systemically and reaches the brain, although at substantially lower levels and with a rapid 24\u2010h clearance. Treatment with \u03b1\u2010SFRP1 had no apparent systemic side effects or sex\u2010dependent differences, but its therapeutic efficacy against AD\u2010like brain pathology was strongly dependent on disease stage. Although early administration reduced amyloid pathology in previous studies, treatment initiated at intermediate or advanced stages showed minimal benefit at standard doses. Higher antibody doses reduced amyloid burden and dystrophic neurites but were associated with increased mortality. Pharmacological inhibition of SFRP1 using a small\u2010molecule inhibitor similarly failed to ameliorate pathology at intermediate stages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Together, these findings demonstrate that SFRP1 remains a relevant therapeutic target in AD, but its effective modulation is constrained by limited brain exposure and a narrow therapeutic window, underscoring the importance of early intervention and prompting the search for improved brain\u2010targeted delivery strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70301","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T09:33:24Z","timestamp":1785231204000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacodynamic and stage\u2010dependent therapeutic efficacy of SFRP1 neutralization in a mouse model of Alzheimer's disease"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0776-1884","authenticated-orcid":false,"given":"Pablo","family":"Miaja","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa CSIC\u2010UAM  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Martinez\u2010Ba\u00f1os","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa CSIC\u2010UAM  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jes\u00fas","family":"Martin\u2010Bermejo","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa CSIC\u2010UAM  Madrid 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