{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:13:52Z","timestamp":1788437632888,"version":"build-2803163510"},"reference-count":64,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T00:00:00Z","timestamp":1709942400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA062203"],"award-info":[{"award-number":["P30CA062203"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["U54 AG054349"],"award-info":[{"award-number":["U54 AG054349"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>INTRODUCTION<\/jats:title><jats:p>The BIN1 coding variant rs138047593 (K358R) is linked to Late\u2010Onset Alzheimer's Disease (LOAD) via targeted exome sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1<jats:sup>K358R<\/jats:sup> knock\u2010in mice using CRISPR\/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The presence of the BIN1<jats:sup>K358R<\/jats:sup> variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild\u2010type and 5xFAD backgrounds homozygous for the BIN1<jats:sup>K358R<\/jats:sup> variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>The BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p><jats:italic>BIN1<\/jats:italic> rs138047593 (K358R) coding variant is associated with increased risk of LOAD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>BIN1 K358R variant increases amyloid plaque load in 12\u2010month\u2010old 5xFAD mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>BIN1 K358R variant decreases neuronal damage in 5xFAD mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13767","type":"journal-article","created":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T12:19:55Z","timestamp":1709986795000},"page":"2922-2942","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["BIN1<sup>K358R<\/sup> suppresses glial response to plaques in mouse model of Alzheimer's disease"],"prefix":"10.1002","volume":"20","author":[{"given":"Laura Fernandez","family":"Garcia\u2010Agudo","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Behavior University of California  Irvine California 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