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In several HD animal models, brain cholesterol biosynthesis and levels are reduced. Since circulating cholesterol cannot reach the brain, providing exogenous cholesterol has been shown to improve HD phenotypes. However, the methods used for cholesterol delivery were invasive and not easily transferable to clinical practice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cholesterol-enriched liposomes were developed by using freeze-and-thaw methods and were administered to R6\/2 mice through a single or repeated intranasal administrations. Deuterated-cholesterol was used to discriminate exogenous from endogenous cholesterol. Exogenous cholesterol accumulation and distribution, as well as the levels of cholesterol precursors and metabolites, were measured using mass spectrometry. Behavioral tests, real-time PCR analysis, and immunostaining of mutant HTT (muHTT) aggregates were performed to verify the therapeutic effects of liposomes. Plasma neurofilament levels were measured by Simoa-Quanterix assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We developed and characterized freeze-and-thaw liposomes. Then, we demonstrate that the exogenous cholesterol can spread throughout the entire brain following intranasal administration of cholesterol-enriched liposomes. Furthermore, repeated intranasal treatments with liposomes result in a full restoration of cognitive decline, and delayed the onset of coordination and motor impairment as well as the loss of muscular strength in the early stages of the disease. Cholesterol supplementation also reduced the plasma level of neurofilament light chain and promoted the clearance of muHTT aggregates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The findings support the effectiveness of cholesterol supplementation as a therapeutic strategy for HD and indicate the translational potential of nose-to-brain cholesterol delivery.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-026-00569-x","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T06:35:56Z","timestamp":1785825356000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington\u2019s disease"],"prefix":"10.1186","volume":"15","author":[{"given":"Monica","family":"Favagrossa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Passoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Valenza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Di Prisco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Birolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Villa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Scolz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Pasetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Bonetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Zuccato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Mariotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo","family":"Bagnati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cattaneo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Colombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9098-9873","authenticated-orcid":false,"given":"Mario","family":"Salmona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"569_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1111\/j.1365-2796.2006.01725.x","volume":"260","author":"I Bj\u00f6rkhem","year":"2006","unstructured":"Bj\u00f6rkhem I. 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