{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T18:57:04Z","timestamp":1788375424942,"version":"build-2803163510"},"reference-count":80,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,7,7]],"date-time":"2024-07-07T00:00:00Z","timestamp":1720310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFE0203000"],"award-info":[{"award-number":["2021YFE0203000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2018YFA0801404"],"award-info":[{"award-number":["2018YFA0801404"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2500103"],"award-info":[{"award-number":["2021YFC2500103"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32100778"],"award-info":[{"award-number":["32100778"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81961128019"],"award-info":[{"award-number":["81961128019"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071187"],"award-info":[{"award-number":["82071187"]}],"id":[{"id":"10.13039\/501100001809","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":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>INTRODUCTION<\/jats:title><jats:p>More robust non\u2010human primate models of Alzheimer's disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We designed a CRISPR\/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3\u2032 and 5\u2032 intron sequences of <jats:italic>PSEN1<\/jats:italic> exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non\u2010human primate model.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We observed early changes of AD\u2010related pathological proteins (cerebrospinal fluid A\u03b2<jats:sub>42<\/jats:sub> and phosphorylated tau) in <jats:italic>PSEN1<\/jats:italic> mutant (ie, <jats:italic>PSEN1<\/jats:italic>\u2010\u0394E9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile <jats:italic>PSEN1<\/jats:italic>\u2010\u0394E9 cynomolgus monkeys.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p><jats:italic>PSEN1<\/jats:italic> mutant cynomolgus monkeys recapitulate AD\u2010related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD\u2010associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>A dual\u2010guide CRISPR\/Cas9 system successfully mimics AD <jats:italic>PSEN1<\/jats:italic>\u2010\u0394E9 mutation by genomic excision of exon 9.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>PSEN1<\/jats:italic> mutant cynomolgus monkey\u2010derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased A\u03b2 secretion.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile <jats:italic>PSEN1<\/jats:italic> mutant cynomolgus monkeys.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Cerebrospinal fluid from juvenile <jats:italic>PSEN1<\/jats:italic> mutant monkeys recapitulates early changes of AD\u2010related pathological proteins (increased A\u03b2<jats:sub>42<\/jats:sub> and phosphorylated tau).<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.14046","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T01:41:10Z","timestamp":1720402870000},"page":"5492-5510","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Early blood immune molecular alterations in cynomolgus monkeys with a PSEN1 mutation causing familial Alzheimer's disease"],"prefix":"10.1002","volume":"20","author":[{"given":"Mengqi","family":"Li","sequence":"first","affiliation":[{"name":"Chinese Academy of Sciences Key Laboratory of Brain Connectome and Manipulation Shenzhen Key Laboratory of Translational Research for Brain Diseases the Brain Cognition and Brain Disease Institute Shenzhen Institute of Advanced Technology Chinese 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