Peptide HDP15 protects against cognitive impairment after ischemia-reperfusion injury by regulating PRKN-mediated mitochondrial autophagy

Post-stroke cognitive impairment (PSCI) involves complex pathophysiology and lacks specific therapeutic approaches. Synaptic plasticity and mitochondrial dysfunction are key pathological mechanisms in PSCI, with mitochondrial autophagy playing a crucial role in maintaining cellular homeostasis. HDP15 is an active, highly conserved peptide secreted by hippocampal neurons. While it is associated with synaptic plasticity, its effects on PSCI remain unknown. To investigate the effects of HDP15 on cognitive impairment following ischemia-reperfusion injury and explore its potential mechanisms. The cerebral middle artery occlusion (MCAO) model was used to evaluate HDP15's impact on neurological function and spatial cognition in rats. Oxygen-glucose deprivation reperfusion (OGD/R) experiments were conducted to study HDP15's regulatory effects on cell viability and mitochondrial function. Results: HDP15 significantly reduced neurological deficits in MCAO rats, shortened escape latency in the Morris water maze, and increased platform crossing attempts, demonstrating marked improvement in spatial cognition. HDP15 enhanced survival rates of OGD/R-treated SH-SY5Y cells, decreased lactate dehydrogenase (LDH) leakage, and upregulated expression of PSD-95, SYP, and α-synuclein. Additionally, HDP15 enhanced mitochondrial function by increasing basal respiration, maximal respiration, and ATP production, while promoting clearance of damaged mitochondria via PRKN-mediated autophagy. HDP15 significantly protects against ischemic stroke by regulating PRKN-mediated mitochondrial autophagy, thereby identifying a new potential target for PSCI treatment.