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One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that the XPO1 inhibitor KPT-330 (Selinexor), an FDA-approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases in\n                    <jats:italic>C. elegans<\/jats:italic>\n                    and\n                    <jats:italic>Drosophila<\/jats:italic>\n                    . Here, we find that KPT-330 increases autophagy in murine neuronal cells. In a murine model of Alzheimer\u2019s disease (5XFAD), KPT-330 improved spatial memory performance. Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that, despite overall increases in amyloid plaque burden, XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.\n                  <\/jats:p>","DOI":"10.1007\/s11357-026-02122-0","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T16:11:01Z","timestamp":1770394261000},"page":"8341-8352","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Spatial memory in Alzheimer\u2019s disease 5XFAD mice is enhanced by XPO1 inhibitor KPT-330"],"prefix":"10.1007","volume":"48","author":[{"given":"Shi Quan","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adia","family":"Ouellette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avery","family":"McNamara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A.","family":"Tam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Alexandrov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Acacia","family":"Nawrocik-Madrid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus J.","family":"Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett C.","family":"Ginsburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo A.","family":"Andrade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8154-141X","authenticated-orcid":false,"given":"Louis R.","family":"Lapierre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"issue":"7","key":"2122_CR1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1007\/s40265-023-01858-9","volume":"83","author":"J Cummings","year":"2023","unstructured":"Cummings J. 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