Hüseyin Tayran, Elanur Yilmaz, Prabesh Bhattarai, Yuhao Min, Xue Wang, Yiyi Ma, Ni Wang, Inyoung Jeong, Nastasia Nelson, Nada Kassara, Mehmet Ilyas Cosacak, Ruya Merve Dogru, Dolly Reyes-Dumeyer, Jakob Mørkved Stenersen, Joseph S Reddy, Min Qiao, Delaney Flaherty, Tamil Iniyan Gunasekaran, Zikun Yang, Nathalie Jurisch-Yaksi, Andrew F Teich, Takahisa Kanekiyo, Giuseppe Tosto, Badri N Vardarajan, Özkan İş, Nilüfer Ertekin-Taner, Richard Mayeux, Caghan Kizil
{"title":"通过 BDNF/NGFR 信号传导，ABCA7 依赖性诱导神经肽 Y 是阿尔茨海默病突触复原力所必需的。","authors":"Hüseyin Tayran, Elanur Yilmaz, Prabesh Bhattarai, Yuhao Min, Xue Wang, Yiyi Ma, Ni Wang, Inyoung Jeong, Nastasia Nelson, Nada Kassara, Mehmet Ilyas Cosacak, Ruya Merve Dogru, Dolly Reyes-Dumeyer, Jakob Mørkved Stenersen, Joseph S Reddy, Min Qiao, Delaney Flaherty, Tamil Iniyan Gunasekaran, Zikun Yang, Nathalie Jurisch-Yaksi, Andrew F Teich, Takahisa Kanekiyo, Giuseppe Tosto, Badri N Vardarajan, Özkan İş, Nilüfer Ertekin-Taner, Richard Mayeux, Caghan Kizil","doi":"10.1016/j.xgen.2024.100642","DOIUrl":null,"url":null,"abstract":"<p><p>Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7<sup>+/-</sup> knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7<sup>-/-</sup> suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1000,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling.\",\"authors\":\"Hüseyin Tayran, Elanur Yilmaz, Prabesh Bhattarai, Yuhao Min, Xue Wang, Yiyi Ma, Ni Wang, Inyoung Jeong, Nastasia Nelson, Nada Kassara, Mehmet Ilyas Cosacak, Ruya Merve Dogru, Dolly Reyes-Dumeyer, Jakob Mørkved Stenersen, Joseph S Reddy, Min Qiao, Delaney Flaherty, Tamil Iniyan Gunasekaran, Zikun Yang, Nathalie Jurisch-Yaksi, Andrew F Teich, Takahisa Kanekiyo, Giuseppe Tosto, Badri N Vardarajan, Özkan İş, Nilüfer Ertekin-Taner, Richard Mayeux, Caghan Kizil\",\"doi\":\"10.1016/j.xgen.2024.100642\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7<sup>+/-</sup> knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7<sup>-/-</sup> suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.</p>\",\"PeriodicalId\":72539,\"journal\":{\"name\":\"Cell genomics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":11.1000,\"publicationDate\":\"2024-08-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell genomics\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xgen.2024.100642\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell genomics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xgen.2024.100642","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling.
Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7+/- knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7-/- suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.
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