The\u00a0R136S\u00a0mutation in the\u00a0APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway<\/a>,\u201d in Immunity, the investigators examined the effects of the mutation\u00a0APOE3-R136S\u2014known as the \u201cChristchurch mutation\u201d\u2014which was recently found to delay hereditary early-onset Alzheimer\u2019s. The scientists showed that the mutation inhibits the cGAS-STING pathway, an innate immune signaling cascade that is abnormally activated in Alzheimer\u2019s and other neurodegenerative diseases. The researchers found that pharmacologically blocking the cGAS-STING pathway with a drug-like inhibitor replicated key protective effects of the mutation in a preclinical model.<\/p>\n![\"Scientists](\"https:\/\/www.europesays.com\/us\/wp-content\/uploads\/2025\/06\/Cornell-Weill.jpg\")
Scientists studying a Colombian family with hereditary early-onset Alzheimer\u2019s, which typically strikes by age 50, reported that one family member, who had two copies of the Christchurch mutation, remained cognitively healthy into her 70s. Despite high brain amyloid, she exhibited low levels of tau. Subsequent research, mostly in mouse models, has confirmed the Christchurch mutation\u2019s beneficial effects\u2014but researchers still aren\u2019t sure how it exerts protection. [Cornell Weill Medicine]\u201cThis is an exciting study because it suggests that inhibiting this cGAS-STING pathway could make the brain more resistant to the Alzheimer\u2019s process, even in the face of significant tau accumulation,\u201d said study senior author Li Gan, PhD, the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases and director of the Helen and Robert Appel Alzheimer\u2019s Disease Research Institute at Weill Cornell Medicine.<\/p>\n
The study\u2019s co-first authors were Sarah Naguib, PhD, Chloe Lopez-Lee, PhD, and Eileen Ruth Torres, PhD, all postdocs in the Gan Laboratory during the study.<\/p>\n
This rare mutation is found in the\u00a0APOE\u00a0gene encoding a cholesterol transport protein (apolipoprotein E), and was first discovered by a laboratory in Christchurch, New Zealand. In 2019, scientists studying a Colombian family with hereditary early-onset Alzheimer\u2019s, which typically strikes by age 50, reported that one family member, who had two copies of the Christchurch mutation, remained cognitively healthy into her 70s. Despite high brain amyloid, she exhibited low levels of tau. Subsequent research, mostly in mouse models, has confirmed the Christchurch mutation\u2019s beneficial effects\u2014but researchers still aren\u2019t sure how it exerts protection.<\/p>\n
In the new study, Gan\u2019s team engineered the Christchurch mutation into the\u00a0APOE\u00a0gene in mice that develop tau accumulation. The researchers found that it protected the animals from hallmark Alzheimer\u2019s features, including tau accumulation, synaptic damage, and disruptions in brain activity. These protective effects were traced to suppression of the cGAS-STING pathway, an innate immune signaling cascade normally activated in response to viral threat but is chronically activated in Alzheimer\u2019s disease.<\/p>\n
\u201cWe are particularly encouraged that this mutation ameliorates disease at the level of brain function, which has not been shown before,\u201d Naguib said.<\/p>\n
Additional finding<\/strong><\/p>\nGan and colleagues further discovered that the protective mechanism of the Christchurch mutation can be largely attributed to taming microglia, brain-resident immune cells. These cells and their inflammatory state in Alzheimer\u2019s have long been seen as potential drivers of the disease process. When the researchers treated mice with tau pathology using a small-molecule inhibitor of cGAS-STING signaling, they observed synapse-protecting effects and molecular changes in brain cells that closely resembled those seen with the protective mutation.<\/p>\n
With mounting evidence that cGAS-STING signaling contributes to disease progression, the team is now exploring its role in other neurodegenerative disorders and testing inhibitors on different animal models of these disorders.<\/p>\n
\u201cWe can\u2019t engineer the rare Christchurch mutation into people to prevent Alzheimer\u2019s,\u201d Gan said, \u201cbut targeting the same pathway it modulates\u2014cGAS-STING\u2014could offer a new therapeutic strategy for Alzheimer\u2019s, and potentially other neurodegenerative conditions.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"Pathological phosphorylation (yellow) of Tau proteins (red-orange) by kinases (violet) leads to disintegration of microtubules in the neuron…\n","protected":false},"author":3,"featured_media":9191,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[26],"tags":[10263,10264,10265,815,10266,50,10262,159,10267,10260,10261,67,132,68],"class_list":{"0":"post-9190","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-alzheimers-disease","9":"tag-gene-mutation","10":"tag-genes","11":"tag-genetics","12":"tag-mice","13":"tag-news","14":"tag-omics","15":"tag-science","16":"tag-signaling-pathway","17":"tag-topics","18":"tag-translational-medicine","19":"tag-united-states","20":"tag-unitedstates","21":"tag-us"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@us\/114735171911995233","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/9190","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/comments?post=9190"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/9190\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media\/9191"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media?parent=9190"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/categories?post=9190"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/tags?post=9190"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
![\"Alzheimers](\"https:\/\/www.europesays.com\/us\/wp-content\/uploads\/2025\/06\/GettyImages-1046071684.jpg\")
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