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

Area of Science:

• Neurobiology
• Cardiology
• Proteomics

Background:

• Cardiovascular diseases (CVDs) are a leading global cause of death.
• CVDs are linked to increased neurodegeneration risk, but underlying mechanisms remain unclear.
• Previous studies showed myocardial infarction (MI) induces protein aggregation and ER stress in the heart and brain.

Purpose of the Study:

• Investigate molecular mechanisms linking MI and neurodegeneration.
• Compare molecular changes in MI mouse models with human Alzheimer's disease (AD) and CVD patient aggregates.
• Identify key proteins and pathways altered by MI and implicated in neurodegeneration.

Main Methods:

• Induced MI in mice and compared to sham-MI controls.
• Proteomic analysis of human hippocampal aggregates from AD, CVD patients, and age-matched controls (AMC).
• Intra-aggregate crosslinking to map protein-protein interactions ('contactomes').
• Leave-one-out analysis (LOOA) to assess protein contribution to aggregate cohesion.
• Gene ontology meta-analyses to identify critical pathways.

Main Results:

• Identified influential proteins in both AD and CVD aggregates.
• Found shared pathways implicated in neurodegeneration, including mitochondrial dysfunction, oxidative stress, ER stress, protein aggregation, and impaired proteostasis (ubiquitin-proteasome system, autophagy).
• Highlighted alterations in axonal transport and synaptic function.

Conclusions:

• MI induces molecular changes in the brain that overlap with those found in human neurodegenerative diseases like AD.
• Protein aggregation and ER stress are key shared mechanisms linking cardiovascular health and brain integrity.
• Findings provide insights into the molecular basis of CVD-associated neurodegeneration.