Investigating in vitro amyloid peptide 1-42 aggregation: impact of higher molecular weight stable adducts

The self-assembly of amyloid peptides (Aβ), in particular Aβ1–42, into oligomers and fibrils is one of the main pathological events related to Alzheimer’s Disease (AD). Recent studies have demonstrated the ability of carbon monoxide releasing molecules (CORMs) to protect neurons and astrocytes from Aβ1-42 toxicity. In fact, CORMs are able to carry and release controlled levels of CO and are known to exert a wide range of anti-inflammatory and anti-apoptotic activities at physiologically relevant concentrations. In order to investigate the direct effects of CORMs on Aβ1–42, we studied the reactivity of CORM-2 and CORM-3 with Aβ1–42 in vitro and the potential inhibition of its aggregation by mass spectrometry (MS), as well as fluorescence and circular dichroism (CD) spectroscopies. The application of an electrospray ionisation-mass spectrometry (ESI-MS) method allowed the detection of stable Aβ1–42/CORMs adducts, involving the addition of the Ru(CO)2 portion of CORMs at histidine residues on the Aβ1-42 skeleton. Moreover, CORMs showed anti-aggregating properties through formation of stable adducts with Aβ1–42 as demonstrated by a thioflavin T (ThT) fluorescence assay and MS analysis. As a further proof, comparison of the CD spectra of Aβ1–42 recorded in the absence and in the presence of CORM-3 at 1:1 molar ratio showed the ability of CORM-3 to stabilize the peptide in its soluble, unordered conformation, thereby preventing its misfolding and aggregation. This multi-methodological investigation revealed novel interactions between Aβ1–42 and CORMs, contributing new insights into the proposed neuroprotective mechanisms mediated by CORMs and disclosing a new strategy to divert amyloid aggregation and toxicity

Multitarget drug design strategy in Alzheimer’s disease: focus on cholinergic transmission and amyloid-β aggregation

Background: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. Results: By exploiting the multitarget approach, the present study provides new molecules able to target the cholinergic pathway, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit Aβ aggregation. Conclusions: These new compounds emerged as a suitable starting point for a further optimization process

The Need of Multidisciplinary Approaches and Engineering Tools for the Development and Implementation of the Smart City Paradigm

This paper is motivated by the concept that the successful, effective, and sustainable implementation of the smart city paradigm requires a close cooperation among researchers with different, complementary interests and, in most cases, a multidisciplinary approach. It first briefly discusses how such a multidisciplinary methodology, transversal to various disciplines such as architecture, computer science, civil engineering, electrical, electronic and telecommunication engineering, social science and behavioral science, etc., can be successfully employed for the development of suitable modeling tools and real solutions of such sociotechnical systems. Then, the paper presents some pilot projects accomplished by the authors within the framework of some major European Union (EU) and national research programs, also involving the Bologna municipality and some of the key players of the smart city industry. Each project, characterized by different and complementary approaches/modeling tools, is illustrated along with the relevant contextualization and the advancements with respect to the state of the art

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS)

Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking

Collaborative and distributed laboratories for remote measurement: concepts and technical challenges

In this paper we address basic concepts and technical challenges toward the realization of a collaborative and distributed network of laborato- ries. This represents an extension of classical re- mote measurement concepts, allowing the realiza- tion of a super-laboratory formed by the integra- tion of features of single laboratories in a transpar- ent manner for the user. We also discuss the possi- bility of remotely de¯ne the object of the measure when implemented with programmable devices as in the case of software de¯ned radio. Two of the major aspect that need to be investigated within the platform of collaborative and distributed labo- ratories are the impact of the communication net- work quality to the measurement quality and the multi user access protocol

Glycogen Synthase Kinase 3\u3b2: A New Gold Rush in Anti-Alzheimer\u2019s Disease Multitarget Drug Discovery?

Alzheimer\u2019s disease (AD), like other multifactorial diseases, is the result of a systemic breakdown of different physiological networks. As result, several lines of evidence suggest that it could be more efficiently tackled by molecules directed toward different dysregulated biochemical targets or pathways. In this context, the selection of targets to which the new molecules will be directed is crucial. For years, the design of such multitarget-directed ligands (MTDLs) has been based on the selection of main targets involved in the \u201ccholinergic\u201d and the \u201c\u3b2-amyloid\u201d hypothesis. Recently, there have been some reports on MTDLs targeting the glycogen synthase kinase 3\u3b2 (GSK-3\u3b2) enzyme, due to its appealing properties. Indeed, this enzyme is involved in tau hyperphosphorylation, controls a multitude of CNS-specific signaling pathways, and establishes strict connections with several factors implicated in AD pathogenesis. In the present Miniperspective, we will discuss the reasons behind the development of GSK-3\u3b2directed MTDLs and highlight some of the recent efforts to obtain these new classes of MTDLs as potential disease-modifying agents

- Application of an ESI-MS method enabling the discovery of new non-ATP competitive GSK-3beta inhibitors.

none4noneDe Simone, A; Milelli, A; Naldi, M; Andrisano, V.De Simone, A; Milelli, A; Naldi, M; Andrisano, V