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Cellular prion protein (PrPC<\/jats:styled-content>) initiates synaptic damage as a high affinity receptor for A\u00dfo. Here, we evaluated the preclinical therapeutic efficacy of a fully human monoclonal antibody against PrPC<\/jats:styled-content>. This AZ<\/jats:styled-content>59 antibody selectively targets the A\u03b2o binding site in the amino\u2010terminal unstructured domain of PrPC<\/jats:styled-content> to avoid any potential risk of direct toxicity.<\/jats:p><\/jats:sec>Methods<\/jats:title>Potency of AZ<\/jats:styled-content>59 was evaluated by binding to PrPC<\/jats:styled-content>, blockade of A\u03b2o interaction and interruption of A\u03b2o signaling. AZ<\/jats:styled-content>59 was administered to mice by weekly intraperitoneal dosing and brain antibody measured. APP<\/jats:styled-content>\/PS<\/jats:styled-content>1 transgenic mice were treated with AZ<\/jats:styled-content>59 and assessed by memory tests, by brain biochemistry and by histochemistry for A\u00df, gliosis and synaptic density.<\/jats:p><\/jats:sec>Results<\/jats:title>AZ<\/jats:styled-content>59 binds PrPC<\/jats:styled-content> with 100\u00a0pmol\/L affinity and blocks human brain A\u00dfo binding to PrPC<\/jats:styled-content>, as well as prevents synaptotoxic signaling. Weekly i.p. dosing of 20\u00a0mg\/kg AZ<\/jats:styled-content>59 in a murine form achieves trough brain antibody levels greater than 10\u00a0nmol\/L. Aged symptomatic APP<\/jats:styled-content>\/PS<\/jats:styled-content>1 transgenic mice treated with AZ<\/jats:styled-content>59 for 5\u20137\u00a0weeks show a full rescue of behavioral and synaptic loss phenotypes. This recovery occurs without clearance of plaque pathology or elimination of gliosis. AZ<\/jats:styled-content>59 treatment also normalizes synaptic signaling abnormalities in transgenic brain. These benefits are dose\u2010dependent and persist for at least 1\u00a0month after the last dose.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>Preclinical data demonstrate that systemic AZ<\/jats:styled-content>59 therapy rescues central synapses and memory function from transgenic Alzheimer's disease pathology, supporting a disease\u2010modifying therapeutic potential.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.730","type":"journal-article","created":{"date-parts":[[2019,2,27]],"date-time":"2019-02-27T08:23:27Z","timestamp":1551255807000},"page":"554-574","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Anti\u2010PrPC<\/sup> antibody rescues cognition and synapses in transgenic alzheimer mice"],"prefix":"10.1002","volume":"6","author":[{"given":"Timothy O.","family":"Cox","sequence":"first","affiliation":[{"name":"Cellular Neuroscience Neurodegeneration & Repair Departments of Neurology and of Neuroscience Yale University School of Medicine New Haven 06536 Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik C.","family":"Gunther","sequence":"additional","affiliation":[{"name":"Cellular Neuroscience Neurodegeneration & Repair Departments of Neurology and of Neuroscience Yale University School of Medicine New Haven 06536 Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Harrison","family":"Brody","sequence":"additional","affiliation":[{"name":"Cellular Neuroscience Neurodegeneration & Repair Departments of Neurology and of Neuroscience Yale University School of Medicine New Haven 06536 Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius T.","family":"Chiasseu","sequence":"additional","affiliation":[{"name":"Cellular Neuroscience Neurodegeneration & Repair Departments of Neurology and of Neuroscience Yale University School of Medicine New Haven 06536 Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"Stoner","sequence":"additional","affiliation":[{"name":"Cellular Neuroscience Neurodegeneration & Repair Departments of Neurology and of Neuroscience Yale University School of Medicine New Haven 06536 Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levi M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Cellular Neuroscience Neurodegeneration & Repair Departments of Neurology and of Neuroscience Yale University School of Medicine New Haven 06536 Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura T.","family":"Haas","sequence":"additional","affiliation":[{"name":"Cellular Neuroscience Neurodegeneration & Repair Departments of Neurology and of Neuroscience Yale University School of Medicine New Haven 06536 Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayne","family":"Hammersley","sequence":"additional","affiliation":[{"name":"Antibody Discovery and Protein Engineering MedImmune Granta Park Cambridge CB21 6GH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth","family":"Rees","sequence":"additional","affiliation":[{"name":"Antibody Discovery and Protein Engineering MedImmune Granta Park Cambridge CB21 6GH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhupinder","family":"Dosanjh","sequence":"additional","affiliation":[{"name":"Antibody Discovery and Protein Engineering MedImmune Granta Park Cambridge CB21 6GH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Groves","sequence":"additional","affiliation":[{"name":"Antibody Discovery and Protein Engineering MedImmune Granta Park Cambridge CB21 6GH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Gardener","sequence":"additional","affiliation":[{"name":"Antibody Discovery and Protein Engineering MedImmune Granta Park Cambridge CB21 6GH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Dobson","sequence":"additional","affiliation":[{"name":"Antibody Discovery and Protein Engineering MedImmune Granta Park Cambridge CB21 6GH 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