Crosstalk between cardiovascular and cognitive diseases: deciphering molecular mechanisms of vascular cognitive impairment

Vascular cognitive impairment (VCI) is a growing public health concern with significant implications for human health. VCI is an understudied complex disease; therefore, this work aims to understand this disease by studying complex molecular interactions between cardiovascular (CVD) and cognitive diseases (CD). This thesis analyzes this crosstalk by building and examining protein-protein interaction (PPI) networks related to CVD and CD. By analyzing alternative protein conformations and mutations in interfaces of interactions, this thesis suggested three mutations in the kinase DYRK1A (V165I, S337P, and D401G) may be essential for VCI via its interaction with APP. Our results indicated that chemokine-related, and stress response-related pathways are likely related to Blood-Brain-Barrier dysregulation in VCI. We found mutant and wild-type VCP, XRCC4, and LIG4 conformations interacting with BRCA1. The analysis of the effect of transcription factors on CVD-CD crosstalk showed that JUN, CREB1, NFKB1, ESR1, and NR3C1 are crucial for VCI regulation, particularly the interaction between the mutant conformation of NFKB1 (structure: 2O61 chain B) and wild-type conformation of NR3C1 structure (3H52 chain B). Lastly, we clustered and predicted disease labels with machine-learning models. We found that GUILD scores and ESMs as features could be crucial when training a model to predict disease labels. Clustering resulted in four clusters enriched in pathways that support our previous results and suggest that RhoGTPase Signaling could play an essential role in the CVD-CD crosstalk and VCI progression. This thesis uncovered biomarkers, protein-protein interactions (protein structures/conformations that interact), and potential therapeutic targets to benefit the scientific and medical communities. This work also proposed pathways linking CVD and CD to suggest new approaches for VCI intervention.