Activation of ACE2 by Hazelnut-Derived Peptide YYLLVR: A Novel Strategy against Hypertension-Induced Cognitive...

Hypertension is a risk factor for cognitive impairment, but the mechanistic link between hypertension and cognitive decline remains unclear. We find that captopril failed to protect against synaptic damage in spontaneously hypertensive rats. In contrast, the hazelnut-derived peptide YYLLVR exerted a dual-modulating effect by activating Angiotensin-converting enzyme 2 (ACE2), simultaneously lowering blood pressure and ameliorating cognitive impairment. YYLLVR reduced mean arterial pressure by 43.18 mmHg (60 mg/kg body weight per day for 4 weeks, P < 0.05). In behavioral tests, it reduced escape latency by 11.29 s and alleviated hippocampal neuronal damage (P < 0.05). YYLLVR inhibited ACE, activated ACE2, suppressed neuroinflammation via glial inactivation, reduced pathological p-tau, and enhanced synaptic plasticity. It also ameliorated mitochondrial dysfunction and oxidative stress across multiple cell lines (100 μM). Molecular dynamics confirmed stable binding of YYLLVR to ACE2. This study establishes a nutritional intervention framework for ACE2-activating peptides against hypertension-induced cognitive impairment.