{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T12:49:14Z","timestamp":1772282954484,"version":"3.50.1"},"posted":{"date-parts":[[2024,6,4]]},"group-title":"Neuroscience","reference-count":90,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Apolipoprotein E \u03b54 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer\u2019s disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer\u2019s Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We introduced the R136S variant into mouse\n                    <jats:italic>Apoe<\/jats:italic>\n                    (\n                    <jats:italic>ApoeCh<\/jats:italic>\n                    ) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial transcriptomics and proteomics to explore the impact of the\n                    <jats:italic>ApoeCh<\/jats:italic>\n                    variant on AD pathological development and the brain\u2019s response to plaques and tau.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    In 5xFAD mice,\n                    <jats:italic>ApoeCh<\/jats:italic>\n                    enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice,\n                    <jats:italic>ApoeCh<\/jats:italic>\n                    suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by\n                    <jats:italic>ApoeCh<\/jats:italic>\n                    . We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of\n                    <jats:italic>ApoeCh<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    These findings highlight the ability of the\n                    <jats:italic>ApoeCh<\/jats:italic>\n                    variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant\u2019s protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.06.03.597211","type":"posted-content","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T17:35:20Z","timestamp":1717522520000},"source":"Crossref","is-referenced-by-count":2,"title":["APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4444-7221","authenticated-orcid":false,"given":"Kristine M.","family":"Tran","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nellie","family":"Kwang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Gomez-Arboledas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shimako","family":"Kawauchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cassandra","family":"Mar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donna","family":"Chao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celia","family":"Da Cunha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuling","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sherilyn","family":"Collins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amber","family":"Walker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai-Xuan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua A.","family":"Alcantara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea J.","family":"Tenner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank M.","family":"LaFerla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsay A.","family":"Hohsfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivek","family":"Swarup","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grant R.","family":"MacGregor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim N.","family":"Green","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024060615200759000_2024.06.03.597211v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"2024060615200759000_2024.06.03.597211v1.2","doi-asserted-by":"crossref","unstructured":"Tanzi, R.E ., The genetics of Alzheimer disease. 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