{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:13:06Z","timestamp":1768511586700,"version":"3.49.0"},"posted":{"date-parts":[[2024,4,28]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,4,28]],"date-time":"2024-04-28T00:00:00Z","timestamp":1714262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,12]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  The Christchurch mutation (R136S) on the\n                  <jats:italic>APOE3<\/jats:italic>\n                  (\n                  <jats:italic>\n                    E3\n                    <jats:sup>S\/S<\/jats:sup>\n                  <\/jats:italic>\n                  ) gene is associated with attenuation of tau load and cognitive decline despite the presence of a causal\n                  <jats:italic>PSEN1<\/jats:italic>\n                  mutation and high levels of amyloid beta pathology in the carrier\n                  <jats:sup>1<\/jats:sup>\n                  . However, the specific molecular mechanisms enabling the\n                  <jats:italic>\n                    E3\n                    <jats:sup>S\/S<\/jats:sup>\n                  <\/jats:italic>\n                  mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse\n                  <jats:italic>ApoE<\/jats:italic>\n                  with wild-type human\n                  <jats:italic>E3<\/jats:italic>\n                  or\n                  <jats:italic>\n                    E3\n                    <jats:sup>S\/S<\/jats:sup>\n                  <\/jats:italic>\n                  on a tauopathy background. The\n                  <jats:italic>R136S<\/jats:italic>\n                  mutation markedly decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in theta and gamma powers. Additionally, the\n                  <jats:italic>R136S<\/jats:italic>\n                  mutation reduced interferon response to tau pathology in both mouse and human microglia, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type\n                  <jats:italic>E3<\/jats:italic>\n                  with a cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the\n                  <jats:italic>R136S<\/jats:italic>\n                  mutation across brain cell types. Thus, suppression of microglial cGAS-STING-IFN pathway plays a central role in mediating the protective effects of\n                  <jats:italic>R136S<\/jats:italic>\n                  against tauopathy.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One-sentence summary<\/jats:title>\n                  <jats:p>The R136S mutation on APOE3 enhances resistance to tau-related pathology and toxicity by downregulating the cGAS-STING-IFN signaling pathway.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.04.25.591140","type":"posted-content","created":{"date-parts":[[2024,4,28]],"date-time":"2024-04-28T16:00:14Z","timestamp":1714320014000},"source":"Crossref","is-referenced-by-count":4,"title":["<i>APOE3<\/i>\n                  -\n                  <i>R136S<\/i>\n                  mutation confers resilience against tau pathology via cGAS-STING-IFN 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