Brain targeting of 9, 11 Conjugated Linoleic Acid, a natural calpain inhibitor, preserves memory and reduces A-beta and P25 accumulation in 5xFAD mice

Deregulation of Cyclin-dependent kinase 5 (CDK5) by binding to the activated calpain product p25, was associated with the onset of neurodegenerative diseases, such as Alzheimer`s disease (AD). Conjugated Linoleic Acid (CLA), a calpain inhibitor, is a metabolite of Punicic Acid (PA), the main component of Pomegranate seed oil (PSO). We have shown recently that long-term administration of Nano-PSO, a nanodroplet formulation of PSO, delays mitochondrial damage and disease advance in a mouse model of genetic Creutzfeldt Jacob disease (CJD). To investigate whether administration of Nano-PSO may target CLA to the brain, we tested its levels in brains of Nano-PSO as compared to PSO treated mice and found that only brains of Nano-PSO treated mice comprise substantial levels of CLA. Next, we tested the cognitive, biochemical and pathological effects of long term administration of Nano-PSO to 5XFAD mice, modeling for AD. We show that administration of Nano-PSO prevented age-related cognitive deterioration and mitochondrial oxidative damage. Brains of treated mice also present reduced accumulation of Amyloid-beta (Aβ) and p25. We conclude that administration of Nano-PSO results in brain targeting of CLA, a natural calpain inhibitor, and suggest that this treatment may prevent/delay the onset of neurodegenerative diseases, such as AD and CJD.