Introduction: Cerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in cerebral vessel walls where it contributes to cerebral hemorrhages and hypoperfusion. We used global, unbiased mass spectrometry-based proteomics to identify proteomic features and biological pathways associated with CAA severity in postmortem blood vessel-enriched compared to parenchyma-enriched brain tissue extracts.

Methods: Brain blood vessel (BV) and parenchymal (PAR) extracts of occipital cortex were obtained from 13 autopsy cases with moderate/severe (n=6) or no/low CAA (n=7) groups. Samples were homogenized, subjected to tryptic digestion, and the resulting peptides analyzed using an Orbitrap Exploris 480 mass spectrometer coupled online to a Dionex UltiMate 3000 system. PEAKS Studio 12 was used for database searching and protein quantification. Limma models were used to compare protein abundance between the two CAA groups. Candidate proteins were defined by a nominal P<0.05 and an absolute fold change of ≥1.3. Gene set enrichment analysis was performed using moderated t-statistics, with significance defined at a Benjamini-Hochberg false discovery rate (FDR)<5%.

Results: A total of 114 BV and 130 PAR proteins met the nominal significance thresholds. When comparing the two CAA groups, most prominent protein changes in BV included those related to Aβ metabolism, vascular remodeling, and immune/clearance processes, including APOE, APP, PTN, SPON1, OLFML3, C3, C4A, and C4B. In contrast, prominent PAR alterations included proteins associated with extracellular matrix remodeling and vascular/immune responses, including FBLN2, LTBP2, STAB1, and SORL1. Functional enrichment analysis indicated significant enrichment of proteins involved in Aβ clearance, synapse organization, gliogenesis, trans-synaptic signaling and immune regulation in BV. In contrast, PAR was associated with enrichment of proteins involved in intermediate filament-based processes and metabolic processes.

Conclusion: Unbiased proteomic profiling revealed distinct vascular and parenchymal signatures associated with CAA, implicating Aβ-related processes, vascular and extracellular matrix remodeling, immune responses, and metabolic alterations in CAA pathology.