Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer's disease.

Alzheimer’s disease Midkine Pleiotrophin aggregation amyloid animal models plaques proteomics

Journal

Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894

Informations de publication

Date de publication:
02 Aug 2024
Historique:
received: 03 08 2023
revised: 15 04 2024
accepted: 10 07 2024
medline: 11 8 2024
pubmed: 11 8 2024
entrez: 10 8 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.xcrm.2024.101669 PMID: 39127040
pubmed: 39127040
pii: S2666-3791(24)00383-5
doi: 10.1016/j.xcrm.2024.101669
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101669

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Yona Levites (Y)

Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Eric B Dammer (EB)

Department of Biochemistry, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Yong Ran (Y)

Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Wangchen Tsering (W)

Department of Pathology, College of Medicine, University of Florida, Gainesville, FL, USA; Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.

Duc Duong (D)

Department of Biochemistry, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Measho Abreha (M)

Department of Biochemistry, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Joshna Gadhavi (J)

Department of Biochemistry, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Kiara Lolo (K)

Department of Pathology, College of Medicine, University of Florida, Gainesville, FL, USA; Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.

Jorge Trejo-Lopez (J)

Department of Pathology, College of Medicine, University of Florida, Gainesville, FL, USA; Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.

Jennifer Phillips (J)

Department of Pathology, College of Medicine, University of Florida, Gainesville, FL, USA; Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.

Andrea Iturbe (A)

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.

Aya Erquizi (A)

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.

Brenda D Moore (BD)

Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Danny Ryu (D)

Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Aditya Natu (A)

Department of Biochemistry, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Kristy Dillon (K)

Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.

Jose Torrellas (J)

Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.

Corey Moran (C)

Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.

Thomas Ladd (T)

Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.

Farhana Afroz (F)

Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Tariful Islam (T)

Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Jaishree Jagirdar (J)

Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, USA.

Cory C Funk (CC)

Institute for Systems Biology, Seattle, WA, USA.

Max Robinson (M)

Institute for Systems Biology, Seattle, WA, USA.

Srikant Rangaraju (S)

Department of Neurology, Yale University, New Haven, CT, USA.

David R Borchelt (DR)

Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.

Nilüfer Ertekin-Taner (N)

Mayo Clinic, Department of Neuroscience, Jacksonville, FL, USA; Mayo Clinic, Department of Neurology, Jacksonville, FL, USA.

Jeffrey W Kelly (JW)

Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.

Frank L Heppner (FL)

Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 110117 Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) Berlin, 110117 Berlin, Germany; Cluster of Excellence, NeuroCure, Charitéplatz, 110117 Berlin, Germany.

Erik C B Johnson (ECB)

Department of Neurology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Karen McFarland (K)

Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Allan I Levey (AI)

Department of Neurology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA.

Stefan Prokop (S)

Department of Pathology, College of Medicine, University of Florida, Gainesville, FL, USA; Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA; Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, USA. Electronic address: sprokop@ufl.edu.

Nicholas T Seyfried (NT)

Department of Biochemistry, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: nseyfri@emory.edu.

Todd E Golde (TE)

Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Department of Neurology, School of Medicine, Emory University, Atlanta, GA, USA; Goizueta Brain Health Institute and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: tgolde@emory.edu.

Classifications MeSH