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Furthermore, dysfunction of plaque-associated microglia, also known as disease-associated microglia (DAM) has been reported to accelerate A\u03b2 deposition and cognitive impairment. Our previous research demonstrated that intermittent hypoxia training (IHT) improved AD pathology by upregulating autophagy in DAM, thereby enhancing oligomeric A\u03b2 (oA\u03b2) clearance. Considering that oA\u03b2 internalization is the initial stage of oA\u03b2 clearance, this study focused on the IHT mechanism involved in upregulating A\u03b2 uptake by DAM.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>IHT was administered to 8-month-old APP\/PS1 mice or 6-month-old microglial vacuolar protein sorting 35 (VPS35) knockout mice in APP\/PS1 background (MG VPS35 KO: APP\/PS1) for 28 days. After the IHT, the spatial learning-memory capacity of the mice was assessed. Additionally, AD pathology was determined by estimating the nerve fiber and synapse density, A\u03b2 plaque deposition, and A\u03b2 load in the brain. A model of A\u03b2-exposed microglia was constructed and treated with IHT to explore the related mechanism. Finally, triggering receptor expressed on myeloid cells 2 (TREM2) intracellular recycling and A\u03b2 internalization were measured using a fluorescence tracing technique.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Our results showed that IHT ameliorated cognitive function and A\u03b2 pathology. In particular, IHT enhanced A\u03b2 endocytosis by augmenting the intracellular transport function of microglial TREM2, thereby contributing to A\u03b2 clearance. Furthermore, IHT specifically upregulated VPS35 in DAM, the primary cause for the enhanced intracellular recycling of TREM2. IHT lost ameliorative effect on A\u03b2 pathology in MG VPS35 KO: APP\/PS1 mice brain. Lastly, the IHT mechanism of VPS35 upregulation in DAM was mediated by the transcriptional regulation of VPS35 by transcription factor EB (TFEB).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>IHT enhances A\u03b2 endocytosis in DAM by upregulating VPS35-dependent TREM2 recycling, thereby facilitating oA\u03b2 clearance and mitigation of A\u03b2 pathology. Moreover, the transcriptional regulation of VPS35 by TFEB demonstrates a close link between endocytosis and autophagy in microglia. Our study further elucidates the IHT mechanism in improving AD pathology and provides evidence supporting the potential application of IHT as a complementary therapy for AD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1186\/s13195-024-01489-6","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T06:02:31Z","timestamp":1717394551000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Intermittent hypoxia training enhances A\u03b2 endocytosis by plaque associated microglia via VPS35-dependent TREM2 recycling in murine Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"16","author":[{"given":"Xueting","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"key":"1489_CR1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.jocn.2020.09.018","volume":"81","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Li Y, Ma L. 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