Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. CVD is known to increase the risk of subsequent neurodegeneration but the mechanism(s) and proteins involved have yet to be elucidated. We previously showed that myocardial infarction (MI), induced in mice and compared to sham-MI mice, leads to increases in protein aggregation, endoplasmic reticulum (ER) stress in both heart and brain, and changes in proteostatic pathways. In this study, we further investigate the molecular mechanisms altered by induced MI in mice, which were also implicated by proteomics of postmortem human hippocampal aggregates from Alzheimer's disease (AD) and cardiovascular disease (CVD) patients, vs. age-matched controls (AMC). We utilized intra-aggregate crosslinking to identify protein-protein contacts or proximities, and thus to reconstruct aggregate "contactomes" (nonfunctional interactomes). We used leave-one-out analysis (LOOA) to determine the contribution of each protein to overall aggregate cohesion, and gene ontology meta-analyses of constituent proteins to define critical organelles, processes, and pathways that distinguish AD and/or CVD from AMC aggregates. We identified influential proteins in both AD and CVD aggregates, many of which are associated with pathways or processes previously implicated in neurodegeneration such as mitochondrial, oxidative, and endoplasmic-reticulum stress; protein aggregation and proteostasis; the ubiquitin proteasome system and autophagy; axonal transport; and synapses.