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

• DOI: 10.1016/j.xcrm.2024.101669
• Publication Date: 2024-08-09T14:40:42Z
• 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-T...; Jeffrey W. Kelly; Frank L. Heppner; Erik C.B. Johnson; Karen McFarland; Allan I. Levey; Stefan Prokop; Nicholas T. Seyfried; Todd E. Golde
• Keywords: Amyloid (mycology)

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 proteome network changes with the proteomes of amyloid β (Aβ)-depositing mice to identify conserved divergent networks identifying an Aβ responsome. Proteins most (M42) accumulate plaques, cerebrovascular (CAA), and/or dystrophic neuronal processes, overexpression two M42 proteins, midkine (Mdk) pleiotrophin (PTN), increases accumulation plaques CAA. proteins bind fibrils vitro, MDK PTN co-accumulate cardiac transthyretin amyloid. appear intimately linked deposition can regulate deposition, suggesting they are pathology modifiers thus putative therapeutic targets. We posit amyloid-scaffolded M42+ central mechanism mediating downstream pathophysiology AD.