Abstract

Deregulation of Cyclin-dependent kinase 5 (CDK5) by binding to the activated calpain product p25, is 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). In this project, we first demonstrated that treatment of mice with Nano-PSO, but not with natural PSO, results in the accumulation of CLA in their brains. Next, we tested the cognitive, biochemical and pathological effects of long-term administration of Nano-PSO to 5XFAD mice, modeling for Alzheimer’s disease. We show that Nano-PSO treatment prevented age-related cognitive deterioration and mitochondrial oxidative damage in 5XFAD mice. Also, brains of the Nano-PSO treated mice presented reduced accumulation of Aβ and of p25, a calpain product, and increased expression of COX IV-1, a key mitochondrial enzyme. We conclude that administration of Nano-PSO results in the brain targeting of CLA, and suggest that this treatment may prevent/delay the onset of neurodegenerative diseases, such as AD and CJD.

Highlights

  • Deregulation of Cyclin-dependent kinase 5 (CDK5) by binding to the activated calpain product p25, is associated with the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD)

  • We have shown recently that long-term administration of Nano-Pomegranate seed oil (PSO) (GranagardTM), a nanodroplet formulation of Pomegranate Seed Oil comprising large levels of Punicic Acid (PA), delayed disease advance significantly in TgMHu2ME199K mice, modeling for genetic Creutzfeldt Jacob disease (CJD) linked to the E200K PrP mutation[13]

  • Our results show that the conversion of PA to Conjugated Linoleic Acid (CLA) in the liver increased significantly when PSO was administrated to the mice as a nano formulation

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Summary

Introduction

Deregulation of Cyclin-dependent kinase 5 (CDK5) by binding to the activated calpain product p25, is associated with the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). We have shown recently that long-term administration of Nano-PSO (GranagardTM), a nanodroplet formulation of Pomegranate Seed Oil comprising large levels of Punicic Acid (PA), delayed disease advance significantly in TgMHu2ME199K mice, modeling for genetic CJD linked to the E200K PrP mutation[13]. Treatment of these genetic mice with Nano-PSO reduced the levels of ROS and restored normal mitochondrial activity and levels of regulatory oxidation factors in brains[14,15]. Nano-PSO treated and untreated 5XFAD or WT mice were assessed for their cognitive status, and subsequently their brains tested for the levels of pathological and biochemical markers such as Aβ, COX IV-1 and p2524

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