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The field of nanomedicine is constantly expanding. Since the first work dated in 1999, almost 28 thousand articles have been published, and more and more are published every year: just think that only in the last five years 20,855 have come out (source PUBMED) including original research and reviews. The goal of this review is to present the current knowledge about nanomedicine in Alzheimer's disease, a widespread neurodegenerative disorder in the over 60 population that deeply affects memory and cognition. Thus, after a brief introduction on the pathology and on the state-of-the-art research for NPs passing the BBB, special attention is placed to new targets that can enter the interest of nanoparticle designers and to new promising therapies. The authors performed a literature review limited to the last three years (2017-2020) of available studies with the intention to present only novel formulations or approaches where at least in vitro studies have been performed. This choice was made because, while limiting the sector to nanotechnology applied to Alzheimer, an organic census of all the relevant news is difficult to obtain.

In the past decade, ketogenic diet (KD) has gained some popularity as a potential treatment for a wide range of diseases, including neurological and metabolic disorders, thanks to a beneficial role mainly related to its anti-inflammatory properties. The high-fat and carbohydrate-restricted regimen causes changes in the metabolism, leading, through the β-oxidation of fatty acids, to the hepatic production of ketone bodies (KBs), which are used by many extrahepatic tissues as energy fuels. Once synthetized, KBs are delivered through the systemic circulation to all the tissues of the organism, where they play pleiotropic roles acting directly and indirectly on various targets, and among them ion channels and neurotransmitters. Moreover, they can operate as signaling metabolites and epigenetic modulators. Therefore, it is inappropriate to consider that the KD regimen can improve the patients’ clinical condition simply by means of specific and localized effects; rather, it is more correct to think that KBs affect the organism as a whole. In this review, we tried to summarize the recent knowledge of the effects of KBs on various tissues, with a particular attention on the excitable ones, namely the nervous system, heart, and muscles.

De novo variants in KCNQ2 encoding for Kv7.2 voltage-dependent neuronal potassium (K+) channel subunits are associated with developmental epileptic encephalopathy (DEE). We herein describe a the clinical and electroencephalographic (EEG) features of a child with early-onset DEE caused by the novel KCNQ2 p.G310S variant. In vitro experiments demonstrated that the mutation induces loss-of-function effects on the currents produced by channels incorporating mutant subunits; these effects were counteracted by the selective Kv7 opener retigabine and by gabapentin, a recently described Kv7 activator. Given these data, the patient started treatment with gabapentin, showing a rapid and sustained clinical and EEG improvement over the following months. Overall, these results suggest that gabapentin can be regarded as a precision therapy for DEEs due to KCNQ2 loss-of-function mutations.

Caveolinopathies are a heterogeneous family of genetic pathologies arising from alterations of the caveolin-3 gene (CAV3), encoding for the isoform specifically constituting muscle caveolae. Here, by reprogramming peripheral blood mononuclear cells, we report the generation of induced pluripotent stem cells (iPSCs) from three patients carrying the ΔYTT deletion, T78K and W101C missense mutations in caveolin-3. iPSCs displayed normal karyotypes and all the features of pluripotent stem cells in terms of morphology, specific marker expression and ability to differentiate in vitro into the three germ layers. These lines thus represent a human cellular model to study the molecular basis of caveolinopathies. Resource table Unique stem cell lines identifier EURACi001-A EURACi002-A EURACi003-A Alternative names of stem cell lines B2CAV3 (EURACi001-A) L1CAV3 (EURACi002-A) N1CAV3 (EURACi003-A) Institution Institute for Biomedicine, Eurac Research Contact information of distributor Alessandra Rossini ( alessandra.rossini@eurac.edu ) Type of cell lines iPSCs Origin Human Cell source Peripheral blood mononuclear cells (PBMCs) Method of reprogramming Electroporation of episomal vectors (pCXLE hOCT3/4-shp53-F, pCXLE-hSK, and pCXLE-hUL) Multiline rationale Non-isogenic cell lines obtained from patients with mutations in the same gene (CAV3) Gene modification NO Type of modification Spontaneous mutations Associated disease Caveolinopathies Gene/locus Heterozygous CAV3 c.Δ184–192 (EURACi001-A) Heterozygous CAV3 c.303 TGG > TGC (EURACi002-A) Heterozygous CAV3 c.233 ACG > AAG (EURACi003-A) Method of modification N/A Name of transgene or resistance N/A Inducible/constitutive system N/A Date archived/stock date January 2016 (EURACi001-A) September 2016 (EURACi002-A) May 2016 (EURACi003-A) Cell line repository/bank N/A Ethical approval Peripheral blood was collected from patients after signing the informed consent provided by Cell Line and DNA Biobank from Patients Affected by Genetic Diseases, member of the Telethon Network of Genetic Biobanks, Istituto G. Gaslini, Genoa, Italy. The generation and use of iPSCs was reviewed and approved by Ethical Committee at Universita’ degli Studi di Milano (03.06.15, number 29/15).

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, ThePaceLab 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±86MΩ in the treated one), a reduction in the rheobase current (from 29.6±3 to 24.2±3pA 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