Gianluigi Forloni
@marionegri.it
Head of Neuroscience Department
Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Dr. Forloni has served as a member of several committees of the European Community for the examination of the projects in the Neuroscience field. He is President of the Italian Association on Brain Aging Research and member of the European Academy of Sciences. He has been in charge of an elective course on genetic of neurodegenerative disorders at the Medical School of the University of Milan, he was invited for lectures and seminars in numerous Universities and Research Centers. Dr. Forloni is the author of more than 325 peer-review scientific (H index Google = 68) articles and about 30 reviews or book chapters.
EDUCATION
1976 Diploma in Industrial Chemistry, Rho (Mi)
1985 Degree in Biological Sciences, University of Milan
RESEARCH INTERESTS
Biological and genetic bases of Alzheimer’s disease (AD), Prion-related encephalopathies (PRE) and Parkinson's disease (PD). Studies on pathogenesis and possible therapeutic approaches based on the role of protein aggregation in the neurodegenerative diseases and mechanisms of neuronal death using in vitro and in vivo models
Scopus Publications
Scopus Publications
Inga Zerr, Anna Ladogana, Simon Mead, Peter Hermann, Gianluigi Forloni, and Brian S. Appleby
Springer Science and Business Media LLC
Silvia De Francesco, Claudio Crema, Damiano Archetti, Cristina Muscio, Robert I. Reid, Anna Nigri, Maria Grazia Bruzzone, Fabrizio Tagliavini, Raffaele Lodi, Egidio D’Angelo,et al.
Springer Science and Business Media LLC
Valeria Veneruso, Emilia Petillo, Fabio Pizzetti, Alessandro Orro, Davide Comolli, Massimiliano De Paola, Antonietta Verrillo, Arianna Baggiolini, Simona Votano, Franca Castiglione,et al.
Wiley
AbstractCurrent treatments for modulating the glial‐mediated inflammatory response after spinal cord injury (SCI) have limited ability to improve recovery. This is quite likely due to the lack of a selective therapeutic approach acting on microgliosis and astrocytosis, the glia components most involved after trauma, while maximizing efficacy and minimizing side effects. A new nanogel that can selectively release active compounds in microglial cells and astrocytes is developed and characterized. The degree of selectivity and subcellular distribution of the nanogel is evaluated by applying an innovative super‐resolution microscopy technique, expansion microscopy. Two different administration schemes are then tested in a SCI mouse model: in an early phase, the nanogel loaded with Rolipram, an anti‐inflammatory drug, achieves significant improvement in the animal's motor performance due to the increased recruitment of microglia and macrophages that are able to localize the lesion. Treatment in the late phase, however, gives opposite results, with worse motor recovery because of the widespread degeneration. These findings demonstrate that the nanovector can be selective and functional in the treatment of the glial component in different phases of SCI. They also open a new therapeutic scenario for tackling glia‐mediated inflammation after neurodegenerative events in the central nervous system.
Laura Tapella, Giulia Dematteis, Pietro La Vitola, Susanna Leva, Elisa Tonelli, Marco Raddi, Marta Delconti, Letizia Dacomo, Alberto La Macchia, Elisa Murari,et al.
Wiley
AbstractAlzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell‐target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD‐related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN‐KO). In the former, we evaluated the ability of β‐amyloid oligomers (AβOs) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN‐KO mice. Next, we generated a tamoxifen‐inducible astrocyte‐specific CaNB1 knock‐out in 3xTg‐AD mice (indACNKO‐AD). CaNB1 was deleted, by tamoxifen injection, in 11.7‐month‐old 3xTg‐AD mice for 4.4 months. Spatial memory was evaluated using the Barnes maze; β‐amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected AβOs in 2‐month‐old wild type mice impaired recognition memory and fostered a pro‐inflammatory microglia phenotype, whereas in ACN‐KO mice, AβOs were inactive. In indACNKO‐AD mice, 4.4 months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte‐specific CaNB1 deletion is beneficial for both the abolishment of AβO‐mediated detrimental effects and treatment of ongoing AD‐related pathology, hence representing an intriguing target for AD therapy.
Silvia De Francesco, Claudio Crema, Damiano Archetti, Cristina Muscio, Robert I. Reid, Anna Nigri, Maria Grazia Bruzzone, Fabrizio Tagliavini, Raffaele Lodi, Egidio D’Angelo,et al.
Springer Science and Business Media LLC
AbstractBiomarker-based differential diagnosis of the most common forms of dementia is becoming increasingly important. Machine learning (ML) may be able to address this challenge. The aim of this study was to develop and interpret a ML algorithm capable of differentiating Alzheimer’s dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal control subjects based on sociodemographic, clinical, and magnetic resonance imaging (MRI) variables. 506 subjects from 5 databases were included. MRI images were processed with FreeSurfer, LPA, and TRACULA to obtain brain volumes and thicknesses, white matter lesions and diffusion metrics. MRI metrics were used in conjunction with clinical and demographic data to perform differential diagnosis based on a Support Vector Machine model called MUQUBIA (Multimodal Quantification of Brain whIte matter biomArkers). Age, gender, Clinical Dementia Rating (CDR) Dementia Staging Instrument, and 19 imaging features formed the best set of discriminative features. The predictive model performed with an overall Area Under the Curve of 98%, high overall precision (88%), recall (88%), and F1 scores (88%) in the test group, and good Label Ranking Average Precision score (0.95) in a subset of neuropathologically assessed patients. The results of MUQUBIA were explained by the SHapley Additive exPlanations (SHAP) method. The MUQUBIA algorithm successfully classified various dementias with good performance using cost-effective clinical and MRI information, and with independent validation, has the potential to assist physicians in their clinical diagnosis.
Gianluigi Forloni
Aging and Disease
In the last few months new results in Alzheimer’s (AD) and Parkinson’s disease (PD) have converged, attracting attention to oligomer species of misfolded proteins, β-amyloid (Aβ and α-synuclein (α-Syn), in the pathogenesis. The high affinity for Aβ protofibrils and oligomers of lecanemab, an antibody recently approved as a disease-modifying drug in AD, and the identification of Aβ-oligomers in blood samples as early biomarkers in subjects with cognitive decline, indicate the oligomers as a therapeutic target and diagnostic tool in AD. α-Syn oligomers were identified by new histopathological techniques in the hippocampus and visual cortex of PD subjects with a distribution distinct from the Lewy body pathologies but associated with cognitive impairment; these species purified from PD brain were highly neurotoxic. In a PD experimental model, we confirmed the presence of α-Syn oligomers associated with cognitive decline and sensitive to drug treatment.
Francesca Fanizza, Lucia Boeri, Francesca Donnaloja, Simone Perottoni, Gianluigi Forloni, Carmen Giordano, and Diego Albani
American Chemical Society (ACS)
Liver-related drug metabolism is a key aspect of pharmacokinetics and possible toxicity. From this perspective, the availability of advanced in vitro models for drug testing is still an open need, also to the end of reducing the burden of in vivo experiments. In this scenario, organ-on-a-chip is gaining attention as it couples a state-of-the art in vitro approach to the recapitulation of key in vivo physiological features such as fluidodynamics and a tri-dimensional cytoarchitecture. We implemented a novel liver-on-a-chip (LoC) device based on an innovative dynamic device (MINERVA 2.0) where functional hepatocytes (iHep) have been encapsulated into a 3D hydrogel matrix interfaced through a porous membrane with endothelial cells (iEndo)]. Both lines were derived from human-induced pluripotent stem cells (iPSCs), and the LoC was functionally assessed with donepezil, a drug approved for Alzheimer’s disease therapy. The presence of iEndo and a 3D microenvironment enhanced the expression of liver-specific physiologic functions as in iHep, after 7 day perfusion, we noticed an increase of albumin, urea production, and cytochrome CYP3A4 expression compared to the iHep static culture. In particular, for donepezil kinetics, a computational fluid dynamic study conducted to assess the amount of donepezil diffused into the LoC indicated that the molecule should be able to pass through the iEndo and reach the target iHep construct. Then, we performed experiments of donepezil kinetics that confirmed the numerical simulations. Overall, our iPSC-based LoC reproduced the in vivo physiological microenvironment of the liver and was suitable for potential hepatotoxic screening studies.
Joanes Grandjean, Gabriel Desrosiers-Gregoire, Cynthia Anckaerts, Diego Angeles-Valdez, Fadi Ayad, David A. Barrière, Ines Blockx, Aleksandra Bortel, Margaret Broadwater, Beatriz M. Cardoso,et al.
Springer Science and Business Media LLC
Yi-Jun Ge, Ya-Nan Ou, Yue-Ting Deng, Bang-Sheng Wu, Liu Yang, Ya-Ru Zhang, Shi-Dong Chen, Yu-Yuan Huang, Qiang Dong, Lan Tan,et al.
Elsevier BV
Massimiliano De Paola, Francesca Pischiutta, Davide Comolli, Alessandro Mariani, Joe Kelk, Ilaria Lisi, Milica Cerovic, Stefano Fumagalli, Gianluigi Forloni, and Elisa R Zanier
SAGE Publications
Brain ischemia is a common acute injury resulting from impaired blood flow to the brain. Translation of effective drug candidates from experimental models to patients has systematically failed. The use of human induced pluripotent stem cells (iPSC) offers new opportunities to gain translational insights into diseases including brain ischemia. We used a human 3D self-assembling iPSC-derived model (human cortical organoids, hCO) to characterize the effects of ischemia caused by oxygen-glucose deprivation (OGD). hCO exposed to 2 h or 8 h of OGD had neuronal death and impaired neuronal network complexity, measured in whole-mounting microtubule-associated protein 2 (MAP-2) immunostaining. Neuronal vulnerability was reflected by a reduction in MAP-2 mRNA levels, and increased release of neurofilament light chain (NfL) in culture media, proportional to OGD severity. Glial fibrillary acidic protein (GFAP) gene or protein levels did not change in hCO, but their release in medium increased after prolonged OGD. In conclusion, this human 3D iPSC-based in vitro model of brain ischemic injury is characterized by marked neuronal injury reflected by the release of the translational biomarker NfL which is relevant for testing neuroprotective strategies.
Joanes Grandjean, Gabriel Desrosiers-Gregoire, Cynthia Anckaerts, Diego Angeles-Valdez, Fadi Ayad, David A. Barrière, Ines Blockx, Aleksandra Bortel, Margaret Broadwater, Beatriz M. Cardoso,et al.
Springer Science and Business Media LLC
Gianluigi Forloni
MDPI AG
Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.
Pietro La Vitola, Luisa Artioli, Milica Cerovic, Cristian Poletto, Letizia Dacomo, Susanna Leva, Claudia Balducci, and Gianluigi Forloni
Elsevier BV
Vincenzo Oliva, Giuseppe Fanelli, Siegfried Kasper, Joseph Zohar, Daniel Souery, Stuart Montgomery, Diego Albani, Gianluigi Forloni, Panagiotis Ferentinos, Dan Rujescu,et al.
Elsevier BV
Fulvia Palesi, Anna Nigri, Ruben Gianeri, Domenico Aquino, Alberto Redolfi, Laura Biagi, Irene Carne, Silvia De Francesco, Stefania Ferraro, Paola Martucci,et al.
Elsevier BV
Marta Lancione, Paolo Bosco, Mauro Costagli, Anna Nigri, Domenico Aquino, Irene Carne, Stefania Ferraro, Giovanni Giulietti, Antonio Napolitano, Fulvia Palesi,et al.
Elsevier BV
Gianluigi Forloni, Pietro La Vitola, and Claudia Balducci
Frontiers Media SA
The central role of oligomers, small soluble aggregates of misfolded proteins, in the pathogenesis of neurodegenerative disorders is recognized in numerous experimental conditions and is compatible with clinical evidence. To underline this concept, some years ago we coined the term oligomeropathies to define the common mechanism of action of protein misfolding diseases like Alzheimer, Parkinson or prion diseases. Using simple experimental conditions, with direct application of synthetic β amyloid or α-synuclein oligomers intraventricularly at micromolar concentrations, we could detect differences and similarities in the biological consequences. The two oligomer species affected cognitive behavior, neuronal dysfunction and cerebral inflammatory reactions with distinct mechanisms. In these experimental conditions the proposed mediatory role of cellular prion protein in oligomer activities was not confirmed. Together with oligomers, inflammation at different levels can be important early in neurodegenerative disorders; both β amyloid and α-synuclein oligomers induce inflammation and its control strongly affects neuronal dysfunction. This review summarizes our studies with β-amyloid or α-synuclein oligomers, also considering the potential curative role of doxycycline, a well-known antibiotic with anti-amyloidogenic and anti-inflammatory activities. These actions are analyzed in terms of the therapeutic prospects.
Stefano Musardo, Sebastien Therin, Silvia Pelucchi, Laura D’Andrea, Ramona Stringhi, Ana Ribeiro, Annalisa Manca, Claudia Balducci, Jessica Pagano, Carlo Sala,et al.
Elsevier BV
Anna Nigri, Stefania Ferraro, Claudia A. M. Gandini Wheeler-Kingshott, Michela Tosetti, Alberto Redolfi, Gianluigi Forloni, Egidio D'Angelo, Domenico Aquino, Laura Biagi, Paolo Bosco,et al.
Frontiers Media SA
Neuroimaging studies often lack reproducibility, one of the cardinal features of the scientific method. Multisite collaboration initiatives increase sample size and limit methodological flexibility, therefore providing the foundation for increased statistical power and generalizable results. However, multisite collaborative initiatives are inherently limited by hardware, software, and pulse and sequence design heterogeneities of both clinical and preclinical MRI scanners and the lack of benchmark for acquisition protocols, data analysis, and data sharing. We present the overarching vision that yielded to the constitution of RIN-Neuroimaging Network, a national consortium dedicated to identifying disease and subject-specific in-vivo neuroimaging biomarkers of diverse neurological and neuropsychiatric conditions. This ambitious goal needs efforts toward increasing the diagnostic and prognostic power of advanced MRI data. To this aim, 23 Italian Scientific Institutes of Hospitalization and Care (IRCCS), with technological and clinical specialization in the neurological and neuroimaging field, have gathered together. Each IRCCS is equipped with high- or ultra-high field MRI scanners (i.e., ≥3T) for clinical or preclinical research or has established expertise in MRI data analysis and infrastructure. The actions of this Network were defined across several work packages (WP). A clinical work package (WP1) defined the guidelines for a minimum standard clinical qualitative MRI assessment for the main neurological diseases. Two neuroimaging technical work packages (WP2 and WP3, for clinical and preclinical scanners) established Standard Operative Procedures for quality controls on phantoms as well as advanced harmonized quantitative MRI protocols for studying the brain of healthy human participants and wild type mice. Under FAIR principles, a web-based e-infrastructure to store and share data across sites was also implemented (WP4). Finally, the RIN translated all these efforts into a large-scale multimodal data collection in patients and animal models with dementia (i.e., case study). The RIN-Neuroimaging Network can maximize the impact of public investments in research and clinical practice acquiring data across institutes and pathologies with high-quality and highly-consistent acquisition protocols, optimizing the analysis pipeline and data sharing procedures.
Oliver Pain, Karen Hodgson, Vassily Trubetskoy, Stephan Ripke, Victoria S. Marshe, Mark J. Adams, Enda M. Byrne, Adrian I. Campos, Tania Carrillo-Roa, Annamaria Cattaneo,et al.
Elsevier BV
Giuseppe Fanelli, Marcus Sokolowski, Danuta Wasserman, Siegfried Kasper, Joseph Zohar, Daniel Souery, Stuart Montgomery, Diego Albani, Gianluigi Forloni, Panagiotis Ferentinos,et al.
Wiley
Suicide is the second cause of death among youths. Genetics may contribute to suicidal phenotypes and their co‐occurrence in other neuropsychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 24 neuropsychiatric, inflammatory, and cardio‐metabolic traits/diseases with suicide attempt (SA) or treatment‐worsening/emergent suicidal ideation (TWESI). PRSs were computed based on summary statistics of genome‐wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts. Results were then meta‐analyzed across samples, including a total of 688 patients with SA (Neff = 2,258) and 214 with TWESI (Neff = 785). Stratified genetic covariance analyses were performed to investigate functionally cross‐phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was associated with SA (OR = 1.24; 95% CI = 1.11–1.38; p = 1.73 × 10−4). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p = 4.6 × 10−3), loneliness (p = .009), or chronic pain (p = .016) and SA, PRSs for MDD or CAD and TWESI (p = .043 and p = .032, respectively). Genetic covariance between MDD and SA was shown in 86 gene sets related to drugs having antisuicidal effects. A higher genetic liability for MDD may underlie a higher SA risk. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.
Marco Calabrò, Chiara Fabbri, Siegfried Kasper, Joseph Zohar, Daniel Souery, Stuart Montgomery, Diego Albani, Gianluigi Forloni, Panagiotis Ferentinos, Dan Rujescu,et al.
Elsevier BV
Vincenzo Oliva, Giuseppe Fanelli, Siegfried Kasper, Joseph Zohar, Daniel Souery, Stuart Montgomery, Diego Albani, Gianluigi Forloni, Panagiotis Ferentinos, Dan Rujescu,et al.
Ovid Technologies (Wolters Kluwer Health)
Social withdrawal is an early manifestation of several neuropsychiatric disorders, and it is characterised by a gradual disengagement from social interactions, potentially leading to complete isolation. This study investigated the association between social withdrawal at baseline and short-term symptom remission in five independent cohorts, including patients with major depressive disorder (MDD), bipolar spectrum disorders, and schizophrenia. Measures of social withdrawal were derived in each study, and clinical remission was estimated based on the psychopathological severity assessed after short-term psychopharmacological treatment (12 weeks). Logistic regression was performed in each sample, adjusting for age and baseline psychopathological severity residualised for social withdrawal. Results were then meta-analysed across samples within a random-effect framework. A total of 4461 patients were included in the analyses (3195 patients with MDD, 655 with bipolar spectrum disorders and 611 with schizophrenia). The meta-analysis showed that higher baseline levels of social withdrawal were associated with a decreased likelihood of short-term remission (ORadj = 0.67, 95% CI, 0.58-0.79, P = 5.28 × 10-7), with the strongest effect in patients with schizophrenia. Overall, our study highlighted the need to address social withdrawal in the early phases of the disease to promote symptom remission in patients with major psychiatric disorders. Understanding the neurobiology underlying social withdrawal may aid the development of medications that can specifically reverse social impairment, thereby fostering clinical remission.
Giuseppe Fanelli, Katharina Domschke, Alessandra Minelli, Massimo Gennarelli, Paolo Martini, Marco Bortolomasi, Eduard Maron, Alessio Squassina, Siegfried Kasper, Joseph Zohar,et al.
Elsevier BV
Gianluigi Forloni, Ignazio Roiter, Vladimiro Artuso, Manuel Marcon, Walter Colesso, Elviana Luban, Ugo Lucca, Mauro Tettamanti, Elisabetta Pupillo, Veronica Redaelli,et al.
Informa UK Limited
ABSTRACT Engaging patients as partners in biomedical research has gradually gained consensus over the last two decades. They provide a different perspective on health priorities and help to improve design and outcomes of clinical studies. This paper describes the relationship established between scientists and members of a large family at genetic risk of very rare lethal disease, fatal familial insomnia (FFI). This interaction led to a clinical trial based on the repurposing of doxycycline – an antibiotic with a known safety profile and optimal blood–brain barrier passage – which in numerous preclinical and clinical studies had given evidence of its potential therapeutic effect in neurodegenerative disorders, including prion diseases like FFI. The design of this trial posed several challenges, which were addressed jointly by the scientists and the FFI family. Potential participants excluded the possibility of being informed of their own FFI genotype; thus, the trial design had to include both carriers of the FFI mutation (10 subjects), and non-carriers (15 subjects), who were given placebo. Periodic clinical controls were performed on both groups by blinded examiners. The lack of surrogate outcome measures of treatment efficacy has required to compare the incidence of the disease in the treated group with a historical dataset during 10 years of observation. The trial is expected to end in 2023. Regardless of the clinical outcome, it will provide worthwhile knowledge on the disease. It also offers an important example of public engagement and collaboration to improve the quality of clinical science.