Physiology, Cellular and Molecular Neuroscience, Neuroscience, Cognitive Neuroscience
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Scopus Publications
Scopus Publications
Intranasal delivery of extracellular vesicles derived from human bone marrow mesenchymal stem cells dampens neuroinflammation and ameliorates motor deficits in a mouse model of cortical stroke Saviana Antonella Barbati, Chiara D'Amelio, Chiara Feroleto, Marta Morotti, Ida Nifo Sarrapochiello, Francesca Natale, Domenica Donatella Li Puma, Yolanda Gomez-Galvez, Elena Blanco-Suarez, Lorraine Iacovitti, Lucia Leone, Salvatore Fusco, Maria Vittoria Podda, Claudio Grassi Experimental Neurology, 2026 Early treatment of ischemic stroke can significantly reduce disability and mortality rates. Stem cell-derived extracellular vesicles (EVs) have shown potential as therapeutics for neurological disorders. This study explored whether intranasal administration of EVs from human bone marrow mesenchymal stem cells (BM-MSCs) enhances forelimb motor function recovery in a mouse model of motor cortex stroke and investigated their mechanism of action, focusing on neuroinflammation. C57BL/6JRj mice received EV treatment of 0.1 × 10 9 EVs per dose per day, 48 h post-stroke and twice weekly for four weeks. EV-treated mice showed significant improvement in forelimb deficits, as evaluated using a series of motor tests. Histopathological assessments revealed reduced infarct volume and decreased astrogliosis and microglial activation in EV-treated mice. EV treatment led to changes in microglial morphology in the peri-infarct area, associated with increased anti-inflammatory cytokines interleukin (IL)-10 and IL-13 and decreased pro-inflammatory cytokines IL-1β, IL-6, and tumor necrosis factor-alpha. Reduced expression of nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome and Cleaved Caspase-1 following EV treatment supports their role in dampening inflammation. In vitro experiments using oxygen-glucose deprivation confirmed that EVs attenuated the inflammatory phenotype of microglia and reduced neuronal apoptosis. EV cargo analysis revealed neuroprotective molecules, including anti-inflammatory cytokines and brain-derived neurotrophic factor (BDNF), which may contribute to their immunomodulatory properties. These findings show that EVs mitigate post-stroke brain immune response, promoting tissue healing and recovery. Our comprehensive characterization of the effects of human BM-MSC-derived EVs, encompassing functional, tissue, cellular, and molecular aspects, underscores their therapeutic potential and supports their use in stroke treatment. • Mesenchymal stem cell-derived extracellular vesicles promote stroke recovery. • Extracellular vesicles reduce glia scar formation and infarct size. • Extracellular vesicles attenuate post-ischemia inflammatory response in microglia. • Extracellular vesicles reduce post-stroke secondary cell death. • Extracellular vesicles mitigate the post-stroke brain immune response.
EEG–motor correlation as early Alzheimer’s disease index in herpes simplex virus type-1–infected mice Chiara D’Amelio, Chiara Feroleto, Chiara Caligiuri, Domenica Donatella Li Puma, Giovanna De Chiara, Ilaria Paoletti, Camilla Codazzi, Federica D’Alelio, Francesca Miraglia, Chiara Pappalettera, Lorenzo Nucci, Federico Frasca, Lucia Ventura, Andrea Manca, Marco Morrone, Lucia Leone, Franca Deriu, Marta Morotti, Claudio Grassi, Fabrizio Vecchio, Maria Vittoria Podda Brain Communications, 2026 Alzheimer's disease is a neurodegenerative disorder characterized by cognitive decline and memory impairment. Early treatment requires reliable tests to identify the initial manifestations for developing treatments that modify disease progression. Neuroinflammation has been implicated as a key driver of the onset and progression of Alzheimer's disease. Herpes simplex virus type-1 (HSV-1), a neurotropic virus that establishes latency within the central nervous system, has been associated with increased proinflammatory cytokines, cognitive impairment and Alzheimer's disease–like pathology in human and rodent brains. This study employed a murine model showing an Alzheimer's disease–related phenotype, induced by HSV-1 infection and recurrent reactivation through thermal stress, to investigate previously unexplored motor function impairments and their correlation with EEG changes predictive of Alzheimer's disease–like pathology. Mice were subjected to two (2×TS) or seven thermal stress (7×TS) HSV-1 reactivations to reproduce mild and severe cognitive impairments, respectively, and were tested for recognition memory using the Novel Object Recognition test and for spatial memory using the Y-maze test. Motor performance was assessed using grip strength and grid walking tests. Local field potential recordings, immunohistochemical, morphological and molecular analyses were performed to characterize the effects of HSV-1 on neural circuits. 2×TS HSV-1 mice showed a reduced preference index in Novel Object Recognition compared to mice receiving mock infection (i.e. vehicle inoculum), whereas 7×TS HSV-1 mice displayed severe cognitive decline across the different memory domains. Motor function was preserved after the second thermal stress but was impaired after the seventh thermal stress, with reduced forelimb force and increased foot faults starting from the fourth reactivation. Following the seventh reactivation, HSV-1 mice showed astrogliosis and phosphorylated Tau accumulation. In vivo, electrophysiological recordings revealed increased functional connectivity across frequency bands in 2×TS HSV-1 mice compared to controls, with negative correlations between total coherence and grip strength. Increased spine density in the frontal cortex of 2×TS HSV-1 mice supports early neuronal network alterations. From a translational perspective, we preliminarily evaluated comparable motor indices in healthy human participants, in patients with mild cognitive impairment, and in patients with Alzheimer's disease. As expected, both grip strength and dynamic balance were lower in patients with Alzheimer's disease compared to healthy and mild cognitive impairment subjects. Notably, grip strength was significantly reduced in mild cognitive impairment subjects, who displayed early motor impairment. Our findings highlight the potential of EEG-based biomarkers for early Alzheimer's disease detection and suggest motor indices as novel prognostic markers.
Navigating the nano-bio immune interface: advancements and challenges in CNS nanotherapeutics Chantalle Moulton, Anna Baroni, Erica Quagliarini, Lucia Leone, Luca Digiacomo, Marta Morotti, Giulio Caracciolo, Maria Vittoria Podda, Ennio Tasciotti Frontiers in Immunology, 2024 In recent years, significant advancements have been made in utilizing nanoparticles (NPs) to modulate immune responses within the central nervous system (CNS), offering new opportunities for nanotherapeutic interventions in neurological disorders. NPs can serve as carriers for immunomodulatory agents or platforms for delivering nucleic acid-based therapeutics to regulate gene expression and modulate immune responses. Several studies have demonstrated the efficacy of NP-mediated immune modulation in preclinical models of neurological diseases, including multiple sclerosis, stroke, Alzheimer’s disease, and Parkinson’s disease. While challenges remain, advancements in NPs engineering and design have led to the development of NPs using diverse strategies to overcome these challenges. The nano-bio interface with the immune system is key in the conceptualization of NPs to efficiently act as nanotherapeutics in the CNS. The biomolecular corona plays a pivotal role in dictating NPs behavior and immune recognition within the CNS, giving researchers the opportunity to optimize NPs design and surface modifications to minimize immunogenicity and enhance biocompatibility. Here, we review how NPs interact with the CNS immune system, focusing on immunosurveillance of NPs, NP-induced immune reprogramming and the impact of the biomolecular corona on NPs behavior in CNS immune responses. The integration of NPs into CNS nanotherapeutics offers promising opportunities for addressing the complex challenges of acute and chronic neurological conditions and pathologies, also in the context of preventive and rehabilitative medicine. By harnessing the nano-bio immune interface and understanding the significance of the biomolecular corona, researchers can develop targeted, safe, and effective nanotherapeutic interventions for a wide range of CNS disorders to improve treatment and rehabilitation. These advancements have the potential to revolutionize the treatment landscape of neurological diseases, offering promising solutions for improved patient care and quality of life in the future.
Early Developmental Changes of Muscle Acetylcholine Receptors Are Little Influenced by Dystrophin Absence in mdx Mouse Marta Morotti, Alessandro Gaeta, Cristina Limatola, Myriam Catalano, Maria Amalia Di Castro, Francesca Grassi Life, 2022 Dystrophin is a cytoskeletal protein contributing to the organization of the neuromuscular junction. In Duchenne muscular dystrophy, due to dystrophin absence, the distribution of endplate acetylcholine receptors (AChRs) becomes disorganized. It is still debated whether this is due to the absence of dystrophin or to the repeated damage/regeneration cycles typical of dystrophic muscle. We addressed this controversy studying the endplate in the first 3 postnatal weeks, when muscle damage in dystrophic (mdx) mice is minimal. By synaptic and extra-synaptic patch-clamp recordings in acutely dissociated mdx and wt muscle fibers, we recorded unitary events due to openings of AChR-channels containing the γ and ε subunit. We also examined AChR distribution at the endplate by immunofluorescence assays. No differences between wt and mdx fibers were found in the γ/ε switch, nor in the AChR organization at the endplates up to 21 postnatal days. Conversely, we detected a delayed appearance and disappearance of patches with high channel opening frequency in mdx fibers. Our data emphasize that the innervation-dependent γ/ε switch and AChR organization in the endplate are not affected by the absence of dystrophin, while extra-synaptic AChR cluster formation and disassembly could be differentially regulated in mdx mice.
Muscle Damage in Dystrophic mdx Mice Is Influenced by the Activity of Ca2+-Activated KCa 3.1 Channels Marta Morotti, Stefano Garofalo, Germana Cocozza, Fabrizio Antonangeli, Valeria Bianconi, Chiara Mozzetta, Maria Egle De Stefano, Riccardo Capitani, Heike Wulff, Cristina Limatola, Myriam Catalano, Francesca Grassi Life, 2022 Duchenne muscular dystrophy (DMD) is an X-linked disease, caused by a mutant dystrophin gene, leading to muscle membrane instability, followed by muscle inflammation, infiltration of pro-inflammatory macrophages and fibrosis. The calcium-activated potassium channel type 3.1 (KCa3.1) plays key roles in controlling both macrophage phenotype and fibroblast proliferation, two critical contributors to muscle damage. In this work, we demonstrate that pharmacological blockade of the channel in the mdx mouse model during the early degenerative phase favors the acquisition of an anti-inflammatory phenotype by tissue macrophages and reduces collagen deposition in muscles, with a concomitant reduction of muscle damage. As already observed with other treatments, no improvement in muscle performance was observed in vivo. In conclusion, this work supports the idea that KCa3.1 channels play a contributing role in controlling damage-causing cells in DMD. A more complete understanding of their function could lead to the identification of novel therapeutic approaches.
The feeding behaviour of Amyotrophic Lateral Sclerosis mouse models is modulated by the Ca2+-activated KCa3.1 channels Germana Cocozza, Stefano Garofalo, Marta Morotti, Giuseppina Chece, Alfonso Grimaldi, Mario Lecce, Ferdinando Scavizzi, Rossella Menghini, Viviana Casagrande, Massimo Federici, Marcello Raspa, Heike Wulff, Cristina Limatola British Journal of Pharmacology, 2021 Background and PurposeAmyotrophic lateral sclerosis (ALS) patients exhibit dysfunctional energy metabolism and weight loss, which is negatively correlated with survival, together with neuroinflammation. However, the possible contribution of neuroinflammation to deregulations of feeding behaviour in ALS has not been studied in detail. We here investigated if microglial KCa3.1 is linked to hypothalamic neuroinflammation and affects feeding behaviours in ALS mouse models.Experimental ApproachhSOD1G93A and TDP43A315T mice were treated daily with 120 mg·kg−1 of TRAM‐34 or vehicle by intraperitoneal injection from the presymptomatic until the disease onset phase. Body weight and food intake were measured weekly. The later by weighing food provided minus that left in the cage. RT‐PCR and immunofluorescence analysis were used to characterize microglia phenotype and the main populations of melanocortin neurons in the hypothalamus of hSOD1G93A and age‐matched non‐tg mice. The cannabinoid–opioid interactions in feeding behaviour of hSOD1G93A mice were studied using an inverse agonist and an antagonist of the cannabinoid receptor CB1 (rimonabant) and μ‐opioid receptors (naloxone), respectively.Key ResultsWe found that treatment of hSOD1G93A mice with the KCa3.1 inhibitor TRAM‐34 (i), attenuates the pro‐inflammatory phenotype of hypothalamic microglia, (ii) increases food intake and promotes weight gain, (iii) increases the number of healthy pro‐opiomelanocortin (POMC) neurons and (iv), changes the expression of cannabinoid receptors involved in energy homeostasis.Conclusion and ImplicationsUsing ALS mouse models, we describe defects in the hypothalamic melanocortin system that affect appetite control. These results reveal a new regulatory role for KCa3.1 to counteract weight loss in ALS.
