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Ultra-low-intensity ultrasound (ULIUS) modulates astrocyte function via transient receptor potential ankyrin 1 (TRPA1) and has been investigated for therapeutic applications in neurodegenerative diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The therapeutic efficacy and mechanisms of ULIUS were evaluated in primary cultured astrocytes and neuron-glia cocultures treated with \u03b1-syn preformed fibrils (PFFs), as well as in an LBD model induced by hippocampal \u03b1-syn PFF injection into neuronal \u03b1-syn-A53T transgenic mice. Astrocytic TRPA1 was modulated under pathologic conditions with ULIUS or a pharmacologic TRPA1 antagonist to determine calcium responses and transcriptional regulation of\n                      <jats:italic>Trpa1<\/jats:italic>\n                      and inflammation-related genes. Neuropathological analyses for Lewy-like inclusions, neurodegeneration, and inflammation were performed in LBD mouse brains, with or without ULIUS. Spatial learning and memory were assessed using the Barnes maze.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Repeated transcranial ULIUS application was safe in long-term use and, unlike prolonged stronger ultrasound, did not cause hippocampal inflammation or neurodegeneration. It also prevented neuroinflammation and Lewy-like pathologies, rescuing cognitive impairment in LBD mice. ULIUS abolished \u03b1-syn-induced elevation of TRPA1, toll-like receptors-2 (TLR2), interleukin-1\u03b2, and tumor necrosis factor-\u03b1 in LBD mouse brains. Mechanistically, both ULIUS and TRPA1 inhibitor blocked the sustained TRPA1-dependent calcium increase and the expression of inflammation-associated transcripts in \u03b1-syn PFF-treated astrocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings provide mechanistic insights into the reciprocal TRPA1\u2013TLR2 signaling pathway in \u03b1-syn-induced astrocyte pathology and underscore the disease-modifying potential of focused transcranial ULIUSm on astrocytes for the treatment of LBD. This study establishes a novel therapeutic strategy to alleviate neuroinflammation and cognitive decline associated with LBD. The demonstration of its long-term safety further supports ULIUS as a promising therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-026-00544-6","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T05:42:17Z","timestamp":1773121337000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ultrasonic repression of TRPA1-dependent astrocyte reactivity confers neuroprotection in models of Lewy body dementia"],"prefix":"10.1186","volume":"15","author":[{"given":"Ji Hun","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keunhyung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minseok","family":"Koo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doeun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin Kyung","family":"Hong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeong-Yun","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han Seok","family":"Ko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joo-Ho","family":"Shin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joo Min","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinhyoung","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0182-2279","authenticated-orcid":false,"given":"Yunjong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"issue":"5","key":"544_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-014-0073-2","volume":"6","author":"WS Kim","year":"2014","unstructured":"Kim WS, Kagedal K, Halliday GM. 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