RAVA ALESSANDRO

PhD Graduate

PhD program:: XXXIII



Thesis title: Impact of cholesterol dyshomeostasis on the physiological functions of developing mouse brain microglia

Background and Aims. Niemann Pick type C disease is a fatal lysosomal storage disorder caused by mutations of NPC1 or NPC2 transporters, which cooperatively mediate the export of endocytosed cholesterol from lysosomes. This leads to the engorgement of lysosomes with cholesterol and other lipids affecting, among others, the autophagic flux. On the other hand, it disrupts the fraction of cholesterol at the level of intracellular compartments and to the plasma membrane, likely affecting a number of signalling mechanisms Although the overt manifestation of the disease is landmarked by neurodegeneration and microgliosis, our recent studies have disclosed significant alterations of development trajectories in the postnatal brain of Npc1-deficient mice, including reduced neurogenic activity, defective synapse connectivity and glial differentiation. Surprisingly, despite the vital role that microglia play in the maturation and maintenance of neuronal circuitry, the issue as to whether the loss of brain homeostasis affects microglia physiological function during postnatal developmental in the Npc1-deficient mice has been poorly explored. The purpose of thesis was to fill this relevant gap in the field. Methods. Exploiting the Npc1nmf164 mouse model on BALB/cJ background, which exhibits a delayed onset and slower disease progression, I have characterized the microglia activation and phagocytic profiles in two areas of the early postnatal brain, the cerebellum (CB) and olfactory bulb (OB), by immunohistological and gene expression analysis. These two regions were selected because they display defective neuronal remodelling in Npc1-deficient mouse models. I have also investigated whether microglia changes associate with functional impairments, by analysing the olfactory performance in complex odour discrimination tasks. Results. My findings demonstrate that depending on the brain homeostasis status at a given developmental stage Npc1-deficient microglia adopt an activated phenotype, characterized by an increased cell proliferation, enlarged soma size and de-ramified processes, as well as a higher phagocytic activity. These changes in microglia activities occur similarly in the CB and OB of Npc1nmf164 mice, despite they are likely induced by region-specific developmental anomalies. Gene expression pattern analyses fully matched microglia activation features. Finally, I found that early microglia activation in the OB is associated to significant defects in the fine odour discriminatory ability of Npc1nmf164 mice. Conclusions: Our results identify microglia activation as an early sign of defective developmental processes in Npc1-deficient mice, further emphasizing that the derangement of developmental trajectories underlies the subsequent appearance of overt signs of the disease. Moreover, our data suggest the employ of challenging olfactory tasks as a valid non-invasive tool to investigate the onset and progression of neurodegenerative diseases, where chemosensory impairment largely precedes the onset of cognitive and motor decline. Key words: Cholesterol, NPC1 transporter, Microglia activation, brain dyshomeostasis

Research products

  • 11573/1122071 - 2016 - Repeated voluntary exercise induces impairments and disease worsening in the low-copy SOD1G93A mouse model of ALS (04f Poster)
    RAVA, ALESSANDRO; PISU, SIMONA; MUSARO', ANTONIO
  • 11573/1122079 - 2018 - PATHOGENETIC MECHANISMS RESPONSIBLE FOR ALTERED DEVELOPMENTAL TRAJECTORIES IN NIEMANN PICK C DISEASE (04d Abstract in atti di convegno)
    CANTERINI, SONIA; DRAGOTTO, JESSICA; LUCARELLI, MICAELA; CAPORALI, PAOLA; RAVA, ALESSANDRO; FIORENZA, MARIA TERESA
  • 11573/1676943 - 2023 - Maternal Immune Activation Induced by Prenatal Lipopolysaccharide Exposure Leads to Long-Lasting Autistic-like Social, Cognitive and Immune Alterations in Male Wistar Rats (01a Articolo in rivista)
    BUZZELLI, VALERIA; MANDUCA, ANTONIA; RAVA, ALESSANDRO; TREZZA, VIVIANA
  • 11573/1291439 - 2019 - Cholesterol dyshomeostasis compromises the physiological functions of glial cells in developing mouse cerebellum: insights from Niemann Pick type C mouse model (04f Poster)
    RAVA, ALESSANDRO; FIORENZA, MARIA TERESA
  • 11573/1291441 - 2019 - Cholesterol dyshomeostasis compromises microglial physiological functions in a mouse model of Niemann Pick type C disease. (04f Poster)
    RAVA, ALESSANDRO; FIORENZA, MARIA TERESA
  • 11573/1335707 - 2019 - The TCL1 function revisited focusing on metabolic requirements of stemness (01g Articolo di rassegna (Review))
    FIORENZA, MARIA TERESA; RAVA, ALESSANDRO
  • 11573/1412210 - 2020 - Altered cerebellar granule cell differentiation and synapse maturation in a mouse model of a lysosomal lipid storage disease. (04f Poster)
    CAMUSO, SERENA; LUCARELLI, MICAELA; RAVA, ALESSANDRO; BABICOLA, LUCY; FIORENZA, MARIA TERESA; CANTERINI, SONIA
  • 11573/1004577 - 2017 - Single prazosin infusion in prelimbic cortex Fosters extinction of amphetamine-induced conditioned place preference (01a Articolo in rivista)
    LATAGLIATA, EMANUELE CLAUDIO; LO IACONO, LUISA; CHIACCHIERINI, GIULIA; RAVA, ALESSANDRO; OLIVA , VALERIA; PUGLISI ALLEGRA, STEFANO
  • 11573/1559647 - 2021 - Postnatal BDNF-mediated cerebellar granule cell development is impaired in a mouse model of Niemann-Pick type C1 disease (04d Abstract in atti di convegno)
    CAMUSO, SERENA; RAVA, ALESSANDRO; TIBERI, JESSICA; LA ROSA, PIERGIORGIO; FIORENZA, MARIA TERESA; CANTERINI, SONIA
  • 11573/1559649 - 2020 - ALTERED CEREBELLAR GRANULE CELL DIFFERENTIATION AND SYNAPSE MATURATION IN A MOUSE MODEL OF A LYSOSOMAL LIPID STORAGE DISEASE (04f Poster)
    CAMUSO, SERENA; LUCARELLI, MICAELA; RAVA, ALESSANDRO; BABICOLA, LUCY; FIORENZA, MARIA TERESA; CANTERINI, SONIA
  • 11573/1551168 - 2020 - ALTERED CEREBELLAR GRANULE CELL DIFFERENTIATION AND SYNAPSE MATURATION IN A MOUSE MODEL OF A LYSOSOMAL LIPID STORAGE DISEASE (04d Abstract in atti di convegno)
    CAMUSO, SERENA; RAVA, ALESSANDRO; BABICOLA, LUCY; FIORENZA, MARIA TERESA; CANTERINI, SONIA
  • 11573/1660553 - 2022 - The appearance of phagocytic microglia in the postnatal brain of Niemann Pick type C mice is developmentally regulated and underscores shortfalls in fine odor discrimination (01a Articolo in rivista)
    RAVA, ALESSANDRO; LA ROSA, PIERGIORGIO; PALLADINO, GIAMPIERO; DRAGOTTO, JESSICA; TIBERI, JESSICA; CANTERINI, SONIA; FIORENZA, MARIA TERESA
  • 11573/1664436 - 2022 - FMR1 deletion in rats induces hyperactivity with no changes in striatal dopamine transporter availability (01a Articolo in rivista)
    MANDUCA, ANTONIA; RAVA, ALESSANDRO; BUZZELLI, VALERIA; GALLI, FILIPPO; SOLURI, ALESSANDRO; TREZZA, VIVIANA
  • 11573/1657118 - 2022 - Anandamide and 2-arachidonoylglycerol differentially modulate autistic-like traits in a genetic model of autism based on FMR1 deletion in rats (01a Articolo in rivista)
    MANDUCA, ANTONIA; BUZZELLI, VALERIA; RAVA, ALESSANDRO; MORENA, MARIA; CAMPOLONGO, PATRIZIA; TREZZA, VIVIANA

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