The activity of neurotrophic factors on their target neurons in the adult and ageing Central Nervous System, as well as their selective availability and transport, represent a cross-road in the mechanisms that lead to neurodegeneration.
|Mouse NGF crystallographic structure (PBD: 1BET) Created with PyMol (www.pymol.org)|
Our laboratory studies how abnormalities in the signalling and post-translational processing of neurotrophins in the CNS are linked to the progressive onset of neurodegeneration. The study of the molecular causes of Alzheimer's disease (AD) is a major theme in the lab, with a common focus on the early events and the upstream mechanistic drivers of AD. The final aim of research in the lab is to build on these mechanistic insights to develop a new generation of therapies for AD and other human neurodegenerative pathologies.
Inspired by the seminal experiments by Rita Levi-Montalcini on immunosympathectomy, our lab has pioneered the use of recombinant antibodies for protein knock-out in the CNS, targeting intracellular antibodies (intrabodies) to achieve protein silencing in different subcellular compartments for mechanistic studies.
By this approach, we created an antiNGF-based transgenic model, demonstrating that selectively interfering with the func¬tion of mature NGF in the adult CNS leads to a progressive neurodegenerative phenotype that recapitulates in a comprehensive way most of the major hallmarks of AD.
|Sezioni di cervello di un topo genticamente modificato nel nostro laboratorio al fine di ottenere un buon modello sperimentale per la malattia di Alzheimer. Gli aggregati marroni rappresentano le aree di neuro degenerazione.|
Studies also showed that neuroinflammatory alterations constitute a significant event very early in the neurodegeneration process in the mouse brain. Recent work by the group, has pointed to the proNGF protein, the processing precursor of mature NGF, as a major player in the neurodegeneration process, whereby an imbalance in the levels of proNGF and NGF in the brain is an upstream driver for neurodegeneration, as part of a circular loop linking proNGF signaling to AD phenotypic endpoints. As part of this endeavour, one of our lines of research investigates the tridimensional structure of proNGF, in order to explain its interaction with the receptors (p75NTR, TrkA, sortilin) and its molecular role in neurodegeneration, by a variety of biophysical techniques.
In this context, the rationale for NGF as a potential therapeutic for AD is very strong. We are pursuing the development of a non invasive therapy for AD, based on the intranasal delivery of NGF, which was demonstrated by our group to be a non invasive, safe and effective mean to achieve pharmacologically active concentrations of NGF in the brain. One liability of NGF as a therapeutics is, however, its well established physiological, pronociceptive activity. This severely limit the doses that can be safely given, in human clinical trials. To circumvent these difficulties, we have engineered painless NGF molecules, inspired by a human genetic mutation found in HSAN V patients, who suffer from a congenital insensitivity to pain and harbor a point mutation in the gene coding for NGF. We have characterized the effect of this mutation on NGF receptor interaction and signaling properties and have engineered an optimized painless NGF that we are now expressing as a recombinant protein and developing for clinical testing in human AD patients.
In collaborative work with Raffaella Scardigli (CNR), the lab is pursuing research on embryonic and adult neurogenesis. As for the former, the aim of this study is to select neuronal progenitors that can be committed to a Motoneuron (MN) fate and then used in transplantation studies in animal models for MN disorders. This knowledge would be of great benefit for the development of new therapeutic strategies for the cure of MN diseases. Concerning adult neurogenesis, we are interested in defining how neurogenesis is regulated in AD, and more specifically in exploring the possibility that NGF might modulate adult neurogenesis in physiological and pathological conditions.
The ultimate goal of this research is to gain new insight into the molecular mechanisms that control adult neurogenesis in response to brain injury such as AD neurodegeneration, and to develop new strategies to restore normal neurogenesis specifically in those brain regions where it is impaired. This information will be of great help for the identification of competent human stem cells with similar potential and thus for the development of cell-replacement strategies for the cure of AD.