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.
Authors
- Tariful Islam (ORCID: https://orcid.org/0000-0002-6459-5301)
- Corey Moran
- Yona Levites (ORCID: https://orcid.org/0000-0001-6925-4525)
- Srikant Rangaraju (ORCID: https://orcid.org/0000-0003-2765-1500)
- Thomas B. Ladd
- Nicholas T. Seyfried (ORCID: https://orcid.org/0000-0002-4507-624X)
- Allan I. Levey (ORCID: https://orcid.org/0000-0002-3153-502X)
- Karen N. McFarland (ORCID: https://orcid.org/0000-0002-9952-8678)
- Wangchen Tsering (ORCID: https://orcid.org/0000-0002-3271-1128)
- David Borchelt (ORCID: https://orcid.org/0000-0002-0813-6979)
- Erik C. B. Johnson (ORCID: https://orcid.org/0000-0002-0604-2944)
- Danny Ryu
- Aditya Natu (ORCID: https://orcid.org/0000-0002-3399-5513)
- Brenda D. Moore (ORCID: https://orcid.org/0000-0002-9685-6561)
- Eric B. Dammer (ORCID: https://orcid.org/0000-0003-2947-7606)
- Kiara Lolo (ORCID: https://orcid.org/0009-0008-7939-8977)
- Todd Eliot Golde (ORCID: https://orcid.org/0000-0003-1867-7071)
- Jorge A. Trejo‐Lopez (ORCID: https://orcid.org/0000-0001-5346-7753)
- Measho Abreha
- Kristy D. Dillon
- Aya Erquizi
- Andrea Iturbe
- Joshna Gadhavi (ORCID: https://orcid.org/0000-0002-7945-4886)
- Nilüfer Ertekin‐Taner (ORCID: https://orcid.org/0000-0003-4436-8889)
- Jeffery W. Kelly (ORCID: https://orcid.org/0000-0001-8943-3395)
- Frank L. Heppner (ORCID: https://orcid.org/0000-0001-9816-8917)
- Cory C. Funk (ORCID: https://orcid.org/0000-0002-5229-9011)
- Max Robinson (ORCID: https://orcid.org/0000-0003-0878-114X)
- Stefan Prokop (ORCID: https://orcid.org/0000-0002-5633-2149)
- Jose Torrellas
- Farhana Afroz
- Yong Ran (ORCID: https://orcid.org/0000-0002-9748-4392)
- Duc M. Duong (ORCID: https://orcid.org/0000-0002-3325-9233)
- Jennifer Phillips
- Jaishree Jagirdar
Institutions
- Scripps Research Institute (US)
- Emory University (US)
- Emory University Hospital (US)
- German Center for Neurodegenerative Diseases (DE)
- Jacksonville College (US)
- WinnMed (US)
- Institute for Systems Biology (US)
- Yale University (US)
- University of Florida (US)
- Humboldt-Universität zu Berlin (DE)
- Mayo Clinic in Florida (US)
- Charité - Universitätsmedizin Berlin (DE)
- Florida College (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101669
- Citations
- 37
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 12.08
Funders
- Alzheimer's Association
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute on Aging