Vitronectin Modulates Plasma Aβ Oligomerization Propensity Within Altered Albumin Interactome Networks in Alzheimer's Disease

초록

Amyloid beta (A beta) oligomers are key mediators of synaptic dysfunction and neural circuit impairment in Alzheimer's disease (AD). While plasma A beta oligomerization propensity (OA beta) correlates with cerebral amyloid pathology and cognitive decline, the systemic modulators of OA beta remain poorly understood. In this study, we identified the albumin interactome (albumin and its associated proteins) as a critical regulator of OA beta. Selective depletion of the albumin interactome from plasma eliminated the OA beta difference between amyloid PET (A-PET)- and A-PET+ individuals. Proteomic analysis revealed widespread network alterations within the albumin interactome of A-PET+ individuals. Notably, vitronectin (VTN) was identified as a key hub protein that was significantly reduced in A-PET+ individuals. Functional assays and in silico modeling demonstrated that VTN directly bound to A beta and inhibited its oligomerization. Additionally, plasma VTN levels distinguished A-PET status. These findings suggest that systemic changes in the albumin interactome, particularly the reduction in VTN, are associated with dysregulated A beta dynamics in plasma. Our results provide novel insights into systemic mechanisms underlying AD pathology and identify VTN as a potential peripheral modulator and biomarker of cerebral amyloid pathology.

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