Multifaceted nanoparticles: emerging mechanisms and therapies in neurodegenerative diseases

Abstract

Neurodegenerative diseases are a major global health burden particularly with the increasing ageing population. Hereditary predisposition and environmental risk factors contribute to the heterogeneity of existing pathological phenotypes. Traditional clinical interventions focused on the use of small drugs have often led to failures due to the difficulties in crossing the blood-brain barrier and reaching the brain. In this regard, nanosystems can specifically deliver drugs and improve their bioavailability, overcoming some of the major challenges in neurodegenerative disease treatment. This review focuses on the use of nanosystems as an encouraging therapeutic approach targeting molecular pathways involved in localized and systematic neurodegenerative diseases. Among the latter, Friedreich's ataxia is an untreatable complex multisystemic disorder and the most widespread type of ataxia; it represents a test case to validate the clinical potential of therapeutic strategies based on nanoparticles with pleiotropic effects.

Keywords: ROS; autophagy; gold quantum clusters; neurodegeneration; neuroinflammation.

Figure 1

NP classification. Schematic representation of organic and inorganic NPs.

Figure 2

Internalization and target pathways of NPs. NPs are internalized by different mechanism, including endocytosis mediated by caveolin vesicles, clathrin vesicles, specific receptors along with phagocytosis and pinocytosis. NPs can enter lysosomes before interacting with other cellular components, such as mitochondria. Finally, NPs can exert their effect on ROS production, mitochondrial metabolism and gene expression.

Figure 3

Action of NPs on neuroinflammation. (A and B) After CNS injury, astrocyte and/or microglia cells activate and promote local inflammation. (C) Persistent inflammation leads to stimulation of cytokine/chemokine storm and activation of inflammatory cells (lymphocytes and monocytes). (D) Inflammatory cells (monocytes, neutrophils, T cells) penetrate the BBB and cause neuroinflammation. NPs might mitigate neuroinflammatory response acting on local inflammation by penetrating the BBB. (E) Neuroinflammation, oxidative stress and excitotoxicity affect neuronal survival and enhance apoptosis by stimulating caspases hyperactivation. NPs can reduce neuronal cell death mitigating caspases hyperactivation. (F) Neuronal dysfunction and inflammatory environment stimulate misfolded protein production and protein aggregate (neurofibrillary tangles, Aβ plaques, Lewy bodies) formation. NPs reduce protein and peptide aggregation and inflammation reducing neuronal toxicity and improving neuronal network and behaviours.

Figure 4

Gold nanoclusters effect in CNS. (A) Au8pX are able to migrate across the BBB acting in different biological pathways (B) such as oxidative stress, autophagy and mitochondrial dynamics. These processes have an indirect effect on frataxin expression.