Abstract

Aims Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. P -coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied. Materials and methods APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip. Results Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of Drp1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis. Conclusions CA-Lip effectively ameliorates hypoxia-induced cognitive impairment by reducing Aβ generation and improving mitochondrial function.