We have been working for some time on the cellular and molecular mechanisms that regulate naturally occurring neuronal death (NOND) in the central nervous system. Our research was initially carried out in vivo and subsequently on cerebellar organotypic cultures. Thus, we demonstrated the existence of two different apoptotic cell death mechanisms affecting the cerebellar granule cells (CGC) during postnatal development. With immunohistochemical and biolistic transfection techniques, we have been able to prove the presence of different apoptotic mechanisms in the proliferating CGCs that populate the external granular layer of the postnatal cerebellar cortex and in the postmitotic CGCs that are located in the internal granular layer, the definitive granular layer of the cerebellar cortex. Using postnatal murine cerebellum cultures, we then analyzed the expression levels of B cell lymphoma protein 2 (BCL-2), one of the most widely studied anti-apoptotic proteins in mammals, whose levels are essential to protect neurons from programmed cell death. We have shown that the cellular content of BCL-2 is regulated post-translationally through a process of autophagy and lysosomal activation. We also developed a new strain of transgenic mice by crossing L7GFP mice, where Purkinje neurons (PN) specifically express the GFP fluorescent protein, and Reeler mutants, which show abnormal PN migration and altered cortical stratification. With this approach we have studied the regulatory mechanisms of NOND for PN and CGC. In these animals, which are considered a useful model for the study of different neuropsychiatric conditions such as autism and schizophrenia, we are also analyzing the neurochemical and circuit changes of the cerebellum during development and in adulthood To better understand the mechanisms of NOND we also tested the death-combating effects of certain grapevine PPs of interest for the oenology and in particular the neuroprotective activity of peonidin- and malvidin-3-O-glucosides, resveratrol, polydatin, quercetin-3-O-glucoside, (+)-taxifolin, and (+)-catechin. In parallel, we are investigating the relationship between proliferation and cell death in older mice to better understand the phenomena of brain aging. Finally, we are studying, with artificial intelligence techniques for the discovery of new molecules, the modulation of the insulin degrading enzyme (IDE) which could, if deficient, lead to an accumulation of Aβ in the brain and therefore appears to be responsible for the onset of Alzheimer's disease in sporadic form.

• Banca d’Italia - Erogazioni liberali 2019

• Lossi L, Merighi A, Novello V, Ferrandino A. - Protective Effects of Some Grapevine Polyphenols against Naturally Occurring Neuronal Death - Molecules 2020 25: E2925.
• Lossi L, Castagna C, Granato A, Merighi A. - The Reeler Mouse: A Translational Model of Human Neurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment? - J Clin Med. 2019 8 :2088.
• Castagna C, Merighi A, Lossi L. - Decreased Expression of Synaptophysin 1 (SYP1 Major Synaptic Vesicle Protein p38) and Contactin 6 (CNTN6/NB3) in the Cerebellar Vermis of reln Haplodeficient Mice - Cell Mol Neurobiol. 2019 39: 833-856.
• Ferrini F, Dering B, De Giorgio A, Lossi L, Granato A. Effects of Acute Alcohol Exposure on Layer 5 Pyramidal Neurons of Juvenile Mice. Cell Mol Neurobiol. 2018 38: 955-963.
• Lossi L, Castagna C, Merighi A. - Caspase-3 Mediated Cell Death in the Normal Development of the Mammalian Cerebellum - Int J Mol Sci. 2018 19: 3999.
• Cocito C, Merighi A, Giacobini M, Lossi L. - Alterations of Cell Proliferation and Apoptosis in the Hypoplastic Reeler Cerebellum - Front Cell Neurosci. 2016 10: 141.
• Lossi L, Cocito C, Alasia S, Merighi A. - Ex vivo imaging of active caspase 3 by a FRET-based molecular probe demonstrates the cellular dynamics and localization of the protease in cerebellar granule cells and its regulation by the apoptosis-inhibiting protein survivin - Mol Neurodegener. 2016 11:34.
• Magliaro C, Cocito C, Bagatella S, Merighi A, Ahluwalia A, Lossi L. - The number of Purkinje neurons and their topology in the cerebellar vermis of normal and reln haplodeficient mouse - Ann Anat. 2016 207: 68-75.
• Castagna C, Merighi A, Lossi L. - Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice - Ann Anat. 2016 207: 76-90.
• Barral S, Beltramo R, Salio C, Aimar P, Lossi L, Merighi A. - Phosphorylation of histone H2AX in the mouse brain from development to senescence - Int J Mol Sci. 2014 15: 1554-1573.

• Prof. Alberto Granato
• Dr. Alessandra Ferrandino - DISAFA
• Dr. Ryan Pemberton - Atomwise Inc. 717 Market St, Suite 800 San Francisco, CA 94103 (USA)