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In this report, we demonstrated pathological changes in retinal M\u00fcller glia significantly earlier than amyloid pathology in AD mouse models. By utilizing the knock\u2010in NLGF mouse model, we surprisingly discovered an increase in reticulon 3 (RTN3) protein levels in the NLGF retina as early as postnatal day 30 (P30). Despite RTN3 being a canonically neuronal protein, this increase was noted in the retinal M\u00fcller glia, confirmed by immunohistochemical characterization. Further unbiased transcriptomic assays of the P30 NLGF retina revealed that retinal M\u00fcller glia were the most sensitive responding cells in this mouse retina, compared with other cell types including photoreceptor cells and ganglion neurons. Pathway analyses of differentially expressed genes in glia cells showed activation of ER stress response via the upregulation of unfolded protein response (UPR) proteins such as ATF4 and CHOP. Early elevation of RTN3 in response to challenges by toxic A\u03b2 likely facilitated UPR. Altogether, these findings suggest that M\u00fcller glia act as a sentinel for AD pathology in the retina and should aid for both intervention and diagnosis.<\/jats:p>","DOI":"10.1002\/glia.24514","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T10:14:58Z","timestamp":1710756898000},"page":"1067-1081","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<scp>ER<\/scp>\u2010stress response in retinal M\u00fcller glia occurs significantly earlier than amyloid pathology in the Alzheimer's mouse brain and retina"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3862-8488","authenticated-orcid":false,"given":"Sarah I.","family":"Palko","sequence":"first","affiliation":[{"name":"Department of Neuroscience University of Connecticut Health Center  Farmington Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc R.","family":"Benoit","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Connecticut Health Center  Farmington Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie Y.","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Connecticut Health Center  Farmington Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Royce","family":"Mohan","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Connecticut Health Center  Farmington Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7195-7617","authenticated-orcid":false,"given":"Riqiang","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Connecticut Health Center  Farmington Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5397-12.2013"},{"key":"e_1_2_9_3_1","article-title":"Dimensionality reduction for visualizing single\u2010cell data using UMAP","author":"Becht E.","year":"2018","journal-title":"Nature Biotechnology"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.611921"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.22"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.30.18060"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-141659"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004924"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105931"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004717"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1089\/jop.2016.0180"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-019-0516-x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-8-2"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-190507"},{"key":"e_1_2_9_16_1","first-page":"705","article-title":"An optimized protocol for retina single\u2010cell RNA sequencing","volume":"26","author":"Fadl B. 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