Neuronal Ryanodine Receptor Type 2: A Pivotal Player in Unraveling the Pathophysiology of Cardiogenic Cognitive Impairment - Project Summary Cognitive impairment (CI) in heart failure (HF) significantly hinders treatment adherence and self-management, particularly in elderly patients with HF. The development of CI in HF is influenced by various factors such as hypertension, atrial fibrillation, stroke, impaired hemodynamics, and neurohormonal signaling defects. Notably, CI is prevalent in both heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). Despite its importance, current evidence on effective treatments to prevent or reduce cognitive decline in HF is still lacking. Our research aims to uncover the mechanisms underlying CI in HF. Interestingly, HF shares pathological traits with neurodegenerative diseases, involving inflammation, oxidative stress, hypoxia, hyper-adrenergic states, and calcium dyshomeostasis. Preliminary studies suggest a leaky phenotype of hippocampal ryanodine receptors (RyR2) in both HFrEF patients and a murine HF model (MI), correlating with deficits in learning and memory. This RyR2 leakiness, also implicated in cognitive dysfunction in Alzheimer's and Huntington's disease, is associated with Tau phosphorylation in both HFrEF patients and MI mice. Proteomic analysis points to dysregulation of calcium-activated proteins in the SNARE pathway, essential for synaptic transmission. MI mice also exhibit impaired hippocampal glucose uptake and long-term potentiation, suggesting that CI in HF is linked to abnormal calcium signaling. We hypothesize that leaky hippocampal RyR2 is a common defect in both HFpEF and HFrEF (both permanent ischemia and ischemia-reperfusion), contributing to cognitive dysfunction in HF. Furthermore, we propose that this RyR2 leakiness is driven by upstream activation of the sympathetic nervous system, inflammation, and TGF-β1 signaling. To explore CI across different HF types, we will employ innovative methodologies, unique mouse models of impaired calcium homeostasis, and available hippocampal tissues from deceased HFpEF patients. Our research goals include characterizing CI in both HFpEF and HFrEF (with ischemia-reperfusion), establishing the role of leaky hippocampal RyR2, identifying the molecular mechanisms behind RyR2 leak and downstream effects, and mitigating CI through genetic and pharmacological interventions. This comprehensive approach aims to uncover new therapeutic targets for CI in HF and improve our understanding of this condition.
