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In an amyloid mouse model, we found that different brain regions formed structurally distinct A\u03b2 deposits, prompting us to test whether neuronal subtypes shape aggregate conformation. To address this, we created transgenic mice expressing the same APP construct in either glutamatergic or GABAergic neurons. APP expression in GABAergic neurons resulted in diffuse plaques with high A\u03b242\/A\u03b240 ratios and minimal gliosis, while glutamatergic expression produced neuritic plaques with activated glia. Despite similar A\u03b2 levels, only mice with neuritic plaques exhibited cognitive deficits. These results show that the neuronal source of APP shapes A\u03b2 plaque structure, influencing both cellular response and behavioral outcome. Our findings affirm that amyloid conformation and gliosis\u2014rather than total A\u03b2 load\u2014drive disease progression, and suggest that regional differences in neuronal composition may govern vulnerability.<\/jats:p>","DOI":"10.1186\/s13024-025-00919-9","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T16:44:29Z","timestamp":1767717869000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuronal subtype governs amyloid structure, cellular response, and cognitive outcome in genetically targeted APP mouse models"],"prefix":"10.1186","volume":"21","author":[{"given":"Gabriella A.","family":"Perez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A.","family":"Edwards III","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob M.","family":"Dundee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon N.","family":"Leahy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuangye","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye-Jin","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Chiao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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