Targeting neuroinflammation in Alzheimer’s disease

Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed every 3.2 seconds. Alzheimer’s disease (AD) accounts for approximately 60%–80% of all dementia cases. Given this evidence, it is clear dementia represents one of the greatest global public health challenges. Currently used drugs alleviate the symptoms of AD but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and tau tangles, new therapeutic approaches have other targets. One of the newest and most promising strategies is the control of reactive gliosis, a multicellular response to brain injury. This phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore their physiological functions and control the neuroinflammatory process offer new therapeutic opportunities for this devastating disease. In this review, we describe the role of neuroinflammation in the AD pathogenesis and progression and then provide an overview of the recent research with the aim of developing new therapies to treat this disorder

Level alignment of a prototypical photocatalytic system: Methanol on TiO2(110)

Photocatalytic and photovoltaic activity depends on the optimal alignment of electronic levels at the molecule/semiconductor interface. Establishing level alignment experimentally is complicated by the uncertain chemical identity of the surface species. We address the assignment of the occupied and empty electronic levels for the prototypical photocatalytic system of methanol on a rutile TiO2 (110) surface. Using many-body quasiparticle (QP) techniques we show that the frontier levels measured in ultraviolet photoelectron and two photon photoemission spectroscopy experiments can be assigned with confidence to the molecularly chemisorbed methanol, rather than its decomposition product, the methoxy species. We find the highest occupied molecular orbital (HOMO) of the methoxy species is much closer to the valence band maximum, suggesting why it is more photocatalytically active than the methanol molecule. We develop a general semi-quantitative model for predicting many-body QP energies based on the appropriate description of electronic screening within the bulk, molecular or vacuum regions of the wavefunctions at molecule/semiconductor interfaces.Comment: 5 pages, 5 figure

Tailoring electronic and optical properties of TiO2: nanostructuring, doping and molecular-oxide interactions

Titanium dioxide is one of the most widely investigated oxides. This is due to its broad range of applications, from catalysis to photocatalysis to photovoltaics. Despite this large interest, many of its bulk properties have been sparsely investigated using either experimental techniques or ab initio theory. Further, some of TiO2's most important properties, such as its electronic band gap, the localized character of excitons, and the localized nature of states induced by oxygen vacancies, are still under debate. We present a unified description of the properties of rutile and anatase phases, obtained from ab initio state of the art methods, ranging from density functional theory (DFT) to many body perturbation theory (MBPT) derived techniques. In so doing, we show how advanced computational techniques can be used to quantitatively describe the structural, electronic, and optical properties of TiO2 nanostructures, an area of fundamental importance in applied research. Indeed, we address one of the main challenges to TiO2-photocatalysis, namely band gap narrowing, by showing how to combine nanostructural changes with doping. With this aim we compare TiO2's electronic properties for 0D clusters, 1D nanorods, 2D layers, and 3D bulks using different approximations within DFT and MBPT calculations. While quantum confinement effects lead to a widening of the energy gap, it has been shown that substitutional doping with boron or nitrogen gives rise to (meta-)stable structures and the introduction of dopant and mid-gap states which effectively reduce the band gap. Finally, we report how ab initio methods can be applied to understand the important role of TiO2 as electron-acceptor in dye-sensitized solar cells. This task is made more difficult by the hybrid organic-oxide structure of the involved systems.Comment: 32 pages, 8 figure

Does neuroinflammation turn on the flame in Alzheimer's disease? Focus on astrocytes

Data from animal models and Alzheimer's disease (AD) subjects provide clear evidence for an activation of inflammatory pathways during the pathogenetic course of such illness. Biochemical and neuropathological studies highlighted an important cause/effect relationship between inflammation and AD progression, revealing a wide range of genetic, cellular, and molecular changes associated with the pathology. In this context, glial cells have been proved to exert a crucial role. These cells, in fact, undergo important morphological and functional changes and are now considered to be involved in the onset and progression of AD. In particular, astrocytes respond quickly to pathology with changes that have been increasingly recognized as a continuum, with potentially beneficial and/or negative consequences. Although it is now clear that activated astrocytes trigger the neuroinflammatory process, however, the precise mechanisms have not been completely elucidated. Neuroinflammation is certainly a multi-faceted and complex phenomenon and, especially in the early stages, exerts a reparative intent. However, for reasons not yet all well known, this process goes beyond the physiologic control and contributes to the exacerbation of the damage. Here we scrutinize some evidence supporting the role of astrocytes in the neuroinflammatory process and the possibility that these cells could be considered a promising target for future AD therapies

On the electronic structure of silicene on Ag substrate: strong hybridization effects

The electronic structure of the recently synthesised (3x3) reconstructed silicene on (4x4) Ag(111) is investigated by first-principles calculations. New states emerge due to the strong hybridization between silicene and Ag. Analyzing the nature and composition of these hybridized states, we show that i) it is possible to clearly distinguish them from states coming from the Dirac cone of free-standing silicene or from the sp-bands of bulk Ag and ii) assign their contribution to the description of the linearly dispersing band observed in photoemission. Furthermore, we show that silicene atoms contribute to the Fermi level, which leads to similar STM patterns as observed below or above the Fermi level. Our findings are crucial for the proper interpretation of experimental observations.Comment: 8 pages, 3 figures including supplementary materia

Neuroendocrine tumors: From anatomopathology to clinical presentation

Anatomopathological classification of Neuroendocrine tumors (NETs), today, covers a pivotal role in correctly identifying the disease and establish the right diagnostic and therapeutic approach it is needed in order to manage the patient. Depending on its grading and staging, NENs can have very different prognostic perspectives. Basing on WHO 2017 classification, in this paper will be explored their main characteristics, diving into main histotypes, dividing them into functional and non-functional tumors, keeping in mind their main locations: gastroenteropancreatic tract and lungs. Their typical clinical presentation and diagnostic strategies will be explained, mainly focusing on nuclear medicine and the importance of receptor overexpression (especially represented by somatostatin receptors, or SSTRs). This is the knowledge on which is based the diagnostic and therapeutic approach with peptide radiopharmaceuticals, especially 68Ga-DOTA-peptides (today, the gold standard in well-differentiated neuroendocrine neoplasms, only with the exception of insulinoma, that shows a low density of these molecules on its cellular surface)

IDENTIFICAZIONE DI NUOVI GENI RESPONSABILI DI MALATTIE RARE DEL NEUROSVILUPPO TRAMITE HOMOZYGOSITY MAPPING E/O SEQUENZIAMENTO DI NUOVA GENERAZIONE

The genetics of most common single-gene neurological disorders has been dissected in the last twenty years. However, the aetiology of several rare Mendelian neurological conditions is still unknown, with significant implications for diagnosis, genetic counselling and therapy. So far the identification of genes for these rare conditions have been constrained by methodological issues, such as the shortage of informative families for linkage analysis, the lack of very dense maps of polymorphic markers and the availability of efficient and low-cost platforms for genotyping and sequencing. Recently, the high-throughput sequencing of the coding DNA (i.e. exome) has been successfully applied to identify causative mutations by comparing the genome-wide profile of non-synonymous variants among unrelated patients affected by the same disease. Thus, exome sequencing may not be readily applicable to patients affected by rare unclassified conditions who cannot be grouped into genetically homogenous pools. To dissect the heterogenous genetic etiology of rare neurological phenotypes, we decided to combine exome sequencing with homozygosity mapping, a robust approach to localize disease genes involved in autosomal recessive (AR) Mendelian disorders in discrete genomic regions. We focused our attention on 7 phenotypic heterogeneity families that they have not been genetically diagnosed of the our Pediatric Neurological Unit. We analyzed variants with standard bioinformatic pipeline and databases of populations as ExAC, GnomaAD, and in-house database (200 normal controls). We confirmed the selected variants by Sanger Sequencing in probands and parents. We excluded the negative variants by Sanger sequencing in affected subjects and parents. In more cases, we demonstrated the pathogenetic role for these variants with functional studies as WesternBlot, staning of tissue and immunofluorescence of the patients\u2019 cells. We generated the Zebrafish model to evaluate the pathogenetic role of some variants. We highlighted the importance of the bioinformatic analysis, which selected the effective genetic causes of pathology in these families. We identified different genes, adding important genotype-phenotype correlations to literature data. In conclusion, this study highlighted a powerful approach for clarify the genetic basis of rare neurological recessive diseases. Furthermore, this genome-wide approach allowed to highlight new genotype-phenotype correlations and expanded the clinical phenotypic spectrum in specificgenetic conditions

Nature-inspired phenolic systems for technological and biomedical applications

The imitation of Nature’s chemical principles and logics has emerged as a competitive strategy for the design and implementation of functional molecular systems and biomaterials for innovative technological and biomedical applications. A unique source of inspiration in this context is offered by phenols, polyphenols and especially catechols, in view of their disparate biological roles. In the last decades, great interest has been directed to understand structural, physical and chemical properties of melanins, the black or brownish-red insoluble polyphenolic pigments of human skin, hair, eyes and melanomas.However, the extreme heterogeneity of their molecular systems and practical difficulties in their extraction and purification processes from natural sources, made their structural characterization and the definition of structure properties relationships a most difficult task. To this aim, synthetic mimics of natural melanins that can be obtained by oxidative polymerization of dopamine (DA), DOPA, 5-Scysteinyldopamine (CDA), 5,6-dihydroxyindole (DHI) or 5,6- dihydroxyindole carboxylic acid (DHICA) hold much promise for technological applications due to their peculiar properties which include a broad-band UV and visible absorption profile, redox properties, free radical scavenging ability and water-dependent hybrid electronic-ionic semiconduction. Of particular relevance for technological purposes is the black polymer produced by oxidation of dopamine, polydopamine (PDA) and inspired by mussels’ unique ability to strongly adhere to rocks underwater via catechol and amine crosslinks from DOPA and lysine residues. Because of its robustness, universal adhesion properties, biocompatibility, reversible and pH switchable permselectivity for both cationic and anionic redox-active probe molecules, PDA based coating technology has opened up the doorway to novel opportunities in the fields of bioengineering, nanomedicine, biosensing and organic electronics. So far, however, progress in polyphenol-, catecholamine- and melanin-based functional materials and systems has been limited by a number of gaps and issues, including: a) the lack of rational strategies based on structure-property relationships for selectively enhancing functionality or imparting new technologically relevant properties to polydopamine and synthetic melanins tailored to applications. b) the lack of detailed studies on the actual scope of previous observations in the literature on catecholamine oxidation chemistry and the coupling with carbon, nitrogen and sulfur nucleophiles; c) the lack of unambiguous data about the specific structural factors underpinning the universal material independent sticking behavior of polydopamine and other mussel inspired bioadhesives. In the light of the foregoing, specific objectives of the present PhD project include: 1) The definition of key structure-property relationships in synthetic eumelanins for the development of rational strategies to enhance or tailor functionality for specific applications; 2) The synthesis and chemical characterization of innovative molecular systems and functional polymers based on rational manipulation of melanin precursors, including dopamine and 5,6-dihydroxyindole for adhesion, crosslinking and other applications; 3) The development of alternative mussel inspired systems for various applications based on the oxidative chemistry of cheap, easily accessible and non-toxic natural phenolic compounds such as caffeic acid and chlorogenic acid; 4) The rational design of novel fluorescence turn-on systems for sensing applications based on catecholamine oxidation chemistry and coupling with nucleophiles. Main results can be summarized as follows: 1) The origin and structure-dependent differences of the main chromophores generated by oxidative polymerization of DHI and DHICA to melanin-type products have been elucidated by a combined experimental and computational approach based on an unprecedented set of dimeric precursors. An improved model for the origin of eumelanin broadband absorption properties has been proposed; 2) The impact of carboxyl group esterification on the structure and antioxidant activity of DHICA-melanins has been clarified for the first time, providing novel directions for the design of melanin-inspired antioxidants and functional systems; 3) The adhesion and pro-oxidant properties of the polymer deriving from CDA oxidation (pCDA) were reported in comparison with PDA. This material proved capable of accelerating the kinetics of autoxidation of glutathione in its reduced form (GSH), a property potentially useful for sensing applications; 4) Two new sulfur-containing analogs of dopamine and 5,6-dihydroxyindole were synthesized, 3,4- dihydroxyphenilethanethiol (DHPET) and 5,6- dihydroxybenzothiophene (DHBT), their oxidative chemistry was investigated and the spectrophotometric, morphological and electronic properties of the DHBT polymer (thiomelanin) were assessed in the frame of a proof-of-concept project on novel melanin-like materials. Part of this work was carried out during a 3-month stay at the Catalan Institute for Nanoscience and Nanotechnologies (ICN2, Bellaterra, Spain) 5) Novel mussel-inspired adhesive films and biocompatible coatings with good metal chelating and dye adsorbing properties were rationally designed and characterized by the autoxidative coupling of the natural catechol caffeic acid with the long-chain hexamethylenediamine at pH 9. The same coupling chemistry was extended to chlorogenic acid and two amino acids, glycine and lysine, for the synthesis of biocompatible green pigments for food-related applications. 6) A pH-sensitive fluorescent thin film and a fluorescent polymer tag were designed and obtained by suitable optimization of the strongly fluorogenic reaction between dopamine and resorcinols. The reaction is efficient, develops from cheap and easily available compounds and can be extended to a range of resorcinol and catecholamine partners. Possible sensing of volatile amines with this fluorogenic system is disclosed. Overall, these results fulfil the main objectives of the PhD project and expand the current repertoire of functional nature-inspired materials and systems

Unimolecular Variant of the Fluorescence Turn-On Oxidative Coupling of Catecholamines with Resorcinols

Reported herein is a unimolecular variant of the fluorescence turn-on oxidative coupling of catecholamines with resorcinols ("FluoResCat") based on the easily accessible conjugate 4-(2-((2,4-dihydroxybenzyl)amino)ethyl)benzene-1,2-diol (1). The process involves an alkali-activatable sequence of autoxidation and intramolecular cyclization steps with loss of carbon, leading to a fluorescent methanobenzofuroazocinone product identical to that obtained from the oxidative coupling of dopamine with resorcinol. A mechanistic route for this unexpected reaction, mimicking the synthesis of the natural fluorophore matlaline, would involve highly constrained polycyclic spiro intermediates (liquid chromatography–mass spectrometry analysis of intermediates, model reactions, and density functional theory calculations). Emission turn-on from 1 in response to oxygen, superoxide-generating systems, or gaseous ammonia/volatile amines may be of interest for sensing applications, for example, in smart packaging