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Here, we present a rapid and flexible alternative using adeno\u2010associated virus (AAV) vectors to express modified prion proteins in PrP\u2010knockout (PrP\u2010KO) mice. Through systematic evaluation of multiple AAV constructs, we optimized vector design by comparing different CNS\u2010specific promoters and regulatory elements to generate prion disease models capable of faithfully propagating the inoculated prion strain. We identified an optimized AAV construct incorporating the human synapsin promoter, MVM enhancer, and WPRE posttranscriptional regulatory element encapsidated in the AAV9P31 serotype to drive neuron\u2010specific expression of modified mouse PrP (W144Y epitope) and bank vole I109 PrP (W145Y epitope). Following intravenous administration, we achieved brain\u2010wide expression at levels comparable to or even exceeding endogenous PrP in some regions. When challenged with mouse\u2010adapted RML prions or human Gerstmann\u2010Str\u00e4ussler\u2010Scheinker (GSS\u2010A117V) disease\u2010causing prions, AAV\u2010PrP mice developed characteristic signs of prion disease with accelerated kinetics (58\u2013106\u2009days post\u2010inoculation for RML; 105\u2013112 dpi for GSS\u2010A117V), displaying features typical of each strain. Serial transmission of AAV\u2010generated RML prions to wild\u2010type mice confirmed preservation of strain\u2010specific properties (165\u2009\u00b1\u20094 dpi), validating the authenticity of prion propagation in this system. This approach provides a versatile platform for rapidly generating and studying prion variants in an authentic brain environment. By reducing model generation time from months to weeks, this system enables accelerated investigation of prion structure\u2013function relationships, strain properties, and therapeutic strategies, with potential applications extending to other protein misfolding diseases.<\/jats:p>","DOI":"10.1111\/bpa.70077","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T08:50:23Z","timestamp":1769849423000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rapid generation of prion disease models using\n                    <scp>AAV<\/scp>\n                    \u2010delivered\n                    <scp>PrP<\/scp>\n                    variants in knockout mice"],"prefix":"10.1111","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7968-510X","authenticated-orcid":false,"given":"Maitena","family":"San\u2010Juan\u2010Ansoleaga","sequence":"first","affiliation":[{"name":"Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Fern\u00e1ndez\u2010Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3476-1855","authenticated-orcid":false,"given":"Jorge M.","family":"Charco","sequence":"additional","affiliation":[{"name":"Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades infecciosas (CIBERINFEC) Carlos III National Health Institute  Madrid Spain"},{"name":"ATLAS Molecular Pharma S. 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