Role of neuronal ryanodine receptor type 2 in cardiogenic dementia

Cognitive dysfunction (CD) in heart failure (HF) adversely affects treatment compliance and self-care. Herein, we show that the ryanodine receptor type 2 (RyR2)/intracellular Ca2+ release channels in patients and mice with HF were remodeled and leaky in hippocampal neurons. RyR2 remodeling was caused by hyperadrenergic stress and activation of the transforming growth factor (TGF-β) pathway. Mice protected against RyR2 Ca2+ leak (RyR2-S2808A) were prevented from CD associated with HF. The downstream effectors of leaky neuronal RyR2 included dysregulation of the SNARE pathway, which orchestrates neurotransmission, and activation of Ca2+-dependent enzymes in the Tau pathway associated with Alzheimer's disease. Fixing RyR2 Ca2+ leak in neurons improved cognitive function in HF mice. Taken together, we propose that HF is a systemic illness characterized by cardiogenic dementia and cardiac and skeletal muscle dysfunction. Intracellular Ca2+ leak is a common effector for all three components of HF.