Novel Curcumin loaded nanoparticles engineered for Blood-Brain Barrier crossing and able to disrupt Abeta aggregates

Ruozi Barbara,Daniela Belletti,Francesca Pederzoli,Martina Masoni,Johannes Keller,Antonio Ballestrazzi,Maria Angela Vandelli,Giovanni Tosi,Andreas M Grabrucker

doi:10.1016/j.ijpharm.2017.05.015

Abstract

The formation of extracellular aggregates built up by deposits of β-amyloid (Aβ) is a hallmark of Alzheimer’s disease (AD). Curcumin has been reported to display anti-amyloidogenic activity, not only by inhibiting the formation of new Aβ aggregates, but also by disaggregating existing ones. However, the uptake of Curcumin into the brain is severely restricted by its low ability to cross the blood-brain barrier (BBB). Therefore, novel strategies for a targeted delivery of Curcumin into the brain are highly desired. Here, we encapsulated Curcumin as active ingredient in PLGA (polylactide-co-glycolic-acid) nanoparticles (NPs), modified with g7 ligand for BBB crossing. We performed in depth analyses of possible toxicity of these NPs, uptake, and, foremost, their ability to influence Aβ pathology in vitro using primary hippocampal cell cultures. Our results show no apparent toxicity of the formulated NPs, but a significant decrease of Aβ aggregates in response to Curcumin loaded NPs. We thus conclude that brain delivery of Curcumin using BBB crossing NPs is a promising future approach in the treatment of AD.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia among an estimated prevalence of 46.8 million people worldwide suffering from some form of dementia in 2015
Our results show no apparent toxicity of the formulated NPs, but a significant decrease of Aβ aggregates in response to Curcumin loaded NPs
AD is a multi-factorial neurodegenerative disorder pathologically characterized by deposits of β-amyloid (Aβ) in senile plaques, intracellular neurofibrillary tangles (NFTs) comprised of hyper-phosphorylated aggregates of microtubule associated with tau protein, synaptic dysfunction, and neuronal death (Schellenberg and Montine, 2012; Perl, 2010; Gallo et al, 2007)

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia among an estimated prevalence of 46.8 million people worldwide suffering from some form of dementia in 2015 (www.alz.co.uk/research/world-report-2016). The amyloid precursor protein (APP) is a transmembrane polypeptide of 770 amino acids. In its physiological form, it is known for neurotrophic activity, while in AD, a pathological deposition of a 42 amino acid long cleavage product of APP, Aβ1-42 occurs. APP is processed into non-aggregating peptides by α-secretases. Genetic predisposition and/or environmental factors lead to differential processing of APP by β- and γ-secretases in AD (Vassar et al, 1999), which results in the formation of mainly extracellular Aβ aggregates. Amyloid plaques are big and inhomogeneous aggregates of Aβ, other peptides, and AGE’s (Advanced Glycation endproducts), which are built by non-enzymatic glycosylation. Synaptic loss as well as a decrease in overall cell number both correlate strongly with cognitive impairment in AD (Butterfield, 1997)

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