Yona Levites, Eric B Dammer, Yong Ran, Wangchen Tsering, Duc Duong, Measho Abreha, Joshna Gadhavi, Kiara Lolo, Jorge Trejo-Lopez, Jennifer Phillips, Andrea Iturbe, Aya Erquizi, Brenda D Moore, Danny Ryu, Aditya Natu, Kristy Dillon, Jose Torrellas, Corey Moran, Thomas Ladd, Farhana Afroz, Tariful Islam, Jaishree Jagirdar, Cory C Funk, Max Robinson, Srikant Rangaraju, David R Borchelt, Nilüfer Ertekin-Taner, Jeffrey W Kelly, Frank L Heppner, Erik C B Johnson, Karen McFarland, Allan I Levey, Stefan Prokop, Nicholas T Seyfried, Todd E Golde
{"title":"整合蛋白质组学发现了阿尔茨海默病中保守的 Aβ 淀粉样蛋白反应蛋白、新型斑块蛋白和病理修饰因子。","authors":"Yona Levites, Eric B Dammer, Yong Ran, Wangchen Tsering, Duc Duong, Measho Abreha, Joshna Gadhavi, Kiara Lolo, Jorge Trejo-Lopez, Jennifer Phillips, Andrea Iturbe, Aya Erquizi, Brenda D Moore, Danny Ryu, Aditya Natu, Kristy Dillon, Jose Torrellas, Corey Moran, Thomas Ladd, Farhana Afroz, Tariful Islam, Jaishree Jagirdar, Cory C Funk, Max Robinson, Srikant Rangaraju, David R Borchelt, Nilüfer Ertekin-Taner, Jeffrey W Kelly, Frank L Heppner, Erik C B Johnson, Karen McFarland, Allan I Levey, Stefan Prokop, Nicholas T Seyfried, Todd E Golde","doi":"10.1016/j.xcrm.2024.101669","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid β (Aβ)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aβ amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aβ in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7000,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer's disease.\",\"authors\":\"Yona Levites, Eric B Dammer, Yong Ran, Wangchen Tsering, Duc Duong, Measho Abreha, Joshna Gadhavi, Kiara Lolo, Jorge Trejo-Lopez, Jennifer Phillips, Andrea Iturbe, Aya Erquizi, Brenda D Moore, Danny Ryu, Aditya Natu, Kristy Dillon, Jose Torrellas, Corey Moran, Thomas Ladd, Farhana Afroz, Tariful Islam, Jaishree Jagirdar, Cory C Funk, Max Robinson, Srikant Rangaraju, David R Borchelt, Nilüfer Ertekin-Taner, Jeffrey W Kelly, Frank L Heppner, Erik C B Johnson, Karen McFarland, Allan I Levey, Stefan Prokop, Nicholas T Seyfried, Todd E Golde\",\"doi\":\"10.1016/j.xcrm.2024.101669\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid β (Aβ)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aβ amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aβ in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. 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Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer's disease.
Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid β (Aβ)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aβ amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aβ in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD.
Cell Reports MedicineBiochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍:
Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine.
Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.