Aβ Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer’s Disease

Abstract

AbstractWe report a highly significant correlation between human Alzheimer’s disease (AD) brain proteome changes and those in CRND8 APP695NL/F transgenic mice. Comparing protein changes observed in the CRND8 mice with co-expression networks derived from human Alzheimer’s disease (AD), reveals both conserved and divergent module changes. Many proteins in the most highly conserved module (M42, matrisome) accumulate in plaques, cerebrovascular amyloid (CAA), dystrophic neuronal processes, or a combination thereof. Overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), in CRND8 mice brains leads to increased accumulation of Aβ in plaques and in blood vessels; further, recombinant MDK and PTN enhance Aβ aggregation into amyloid structures. Multiple M42 proteins bind to fibrillar Aβ42 and a non-human amyloid fibrilin vitro. Supporting this binding data, MDK and PTN co-accumulate with transthyretin (TTR) amyloid in the heart. Notably, our findings establish that proteomic changes in modules observed in human AD brains define an Aβ amyloid “responsome” that is well conserved from mouse models to humans. Further, distinct amyloid structures appear to serve as scaffolds, facilitating the co-accumulation of proteins with signaling functions, and this co-accumulation may contribute to downstream pathological sequalae. Overall, this contextualized understanding of proteomic changes and their interplay with amyloid deposition provides valuable insights into the complexity of AD pathogenesis and potential biomarkers and therapeutic targets.