Modulation of the intrinsic neuronal excitability by multifunctional liposomes tailored for the treatment of Alzheimer's disease

Abstract

Anna Binda,1 Alice Panariti,1 Andrea Barbuti,2 Carmen Murano,1 Roberta Dal Magro,1 Massimo Masserini,1,3,4 Francesca Re,1,3,4 Ilaria Rivolta,1,3,4 1School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; 2Department of Biosciences, The PaceLab and Interuniversity Center of Molecular Medicine and Applied Biophysics (CIMMBA), University of Milan, Milano, Italy; 3Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Monza, Italy; 4Nanomedicine Center NANOMIB, University of Milano-Bicocca, Milano, Italy Purpose: Nanotechnologies turned out to be promising in the development of diagnostic and therapeutic approaches toward neurodegenerative disorders. However, only a very scant number of nanodevices until now proved to be effective on preclinical animal models. Although specific tests in vivo are available to assess the potential toxicity of these nanodevices on cognitive functions, those to evaluate their biosafety in vitro on neurons are still to be improved. Materials and methods: We utilized the patch-clamp technique on primary cultures of cortical neural cells isolated from neonatal rats, aiming to evaluate their electrical properties after the incubation with liposomes (mApoE-PA-LIPs), previously proved able to cross the blood–brain barrier and to be effective on mouse models of Alzheimer’s disease (AD), both in the absence and in the presence of β-amyloid peptide oligomers. Results: Data show a high degree of biocompatibility, evaluated by lactate dehydrogenase (LDH) release and MTT assay, and the lack of cellular internalization. After the incubation with mApoE-PA-LIPs, neuronal membranes show an increase in the input resistance (from 724.14±76 MΩ in untreated population to 886.06±86 MΩ in the treated one), a reduction in the rheobase current (from 29.6±3 to 24.2±3 pA in untreated and treated, respectively), and an increase of the firing frequency, consistent with an ultimate increase in intrinsic excitability. Data obtained after co-incubation of mApoE-PA-LIPs with β-amyloid peptide oligomers suggest a retention of liposome efficacy. Conclusion: These data suggest the ability of liposomes to modulate neuronal electrical properties and are compatible with the previously demonstrated amelioration of cognitive functions induced by treatment of AD mice with liposomes. We conclude that this electrophysiological approach could represent a useful tool for nanomedicine to evaluate the effect of nanoparticles on intrinsic neuronal excitability. Keywords: neurodegenerative disorders, nanomedicine, action potential, electrophysiology, patch clamp, β-amyloid peptide

Keywords

• neurodegenerative disorders
• nanomedicine
• action potential
• electrophysiology
• patch clamp
• β-amyloid peptide