Brain development and disease

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Group leader:  Alessandro Vercelli



My-AHA - My Active and Healthy Ageing
January 2016-2019 | Horizon 2020

Coordinator Alessandro Vercelli, NICO - University of Torino
The consortium is made of: Istituto Mario Boella (Torino), the Universities of Siegen and Koln (D), Loughborough (GB), Instituto de Biomecanica Valencia (E), Fraunhofer Portugal, Johanniter Austerreich (A), Kasa Solution (D), VitalinQ (N), GESMED (E). To the consortium participate as Extra-EU partners Seul National University (South Korea), Tohoku University (Japan), University of the Sunshine Coast (Australia), and the JIN company (Japan).

Aims and Relevance
The main aim of my-AHA is to reduce frailty risk by improving physical activity and cognitive function, psychological state, social resources, nutrition, sleep and overall well-being. It will empower older citizens to better manage their own health, resulting in healthcare cost savings. my-AHA will use state-of-the-art analytical concepts to provide new ways of health monitoring and disease prevention through individualized profiling and personalized recommendations, feedback and support.

An ICT-based platform will detect defined risks in the frailty domains early and accurately via non-stigmatising embedded sensors and data readily available in the daily living environment of older adults. When risk is detected, my-AHA will provide targeted ICT-based interventions with a scientific evidence base of efficacy, including vetted offerings from established providers of medical and AHA support. These interventions will follow an integrated approach to motivate users to participate in exercise, cognitively stimulating games and social networking to achieve long-term behavioural change, sustained by continued end user engagement with my-AHA.
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Neurostemcellrepair - European stem cell consortium for neural cell replacement, reprogramming and functional brain repair
2013-2017 | FP7 European Union

E Fucà, A Buffo, D Carulli participating in the research unit headed by A Vercelli
 Research network: Elena Cattaneo, University of Milan, coordinator, Ernest Arenas, Karoliska Institute, deputy coordinator, Parmar Malin, University of Lund, Stephen Dunnet, University of Cardiff, Oliver Brustle, University of Bonn, Roger Barker, University of Cambridge, Charles ffrench-Constant, University of Edimburgh, Andreas Bosio, Milteny, Ida Biunno, Isenet).

This project aims at developing new strategies for stem cell therapies in Hungtington and Parkinson diseases, including acquisition of specific neuronal identities and functional integration in the recipient brain. We contribute our expertise in rodent models of Hungtington disease, and analyse how specific training activities can ameliorate differentiation and integration of grafted cells.
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Motor neuron death in Spinal Muscular Atrophy (SMA): new animal models and innovative therapeutic strategies
2011-2015 | Italian Ministry of Health RF-2009-1475235

The proposed research project will aggregate: i) the Molecular Neuroanatomy and Pathogenesis Unit (G. Battaglia), at the IRCCS Foundation Neurological Institute "C. Besta" in Milano; ii) the Molecular and Computational Biology lab (F. Di Cunto) at the Molecular Biotechnology Center in Torino; iii) the C.elegans Neurobiology lab (E. Di Schiavi) at the Institute of Genetics and Biophysics of the CNR in Napoli; and iv) the lab of Developmental Neuroanatomy (A. Vercelli) at the NICO.

Spinal Muscular Atrophy or SMA is a severe autosomal recessive disease characterized by selective motor neuron degeneration. SMA is the leading genetic cause of infant mortality, with an incidence of 1:10.000 live births and an estimated carrier frequency of 1:35. The SMA determining gene was discovered in 1995 and termed survival motor neuron (SMN) gene.
The main protein product of the SMN1 gene, the FL-SMN protein, has its primary and most important role in spliceosomal assembly and pre-mRNAs maturation. However, how reduced FL-SMN levels lead to selective degeneration of motor neurons in SMA still remains elusive. Accordingly, no effective therapy is up to now available for affected children.
A novel, truncated isoform of the FL-SMN protein, a-SMN or axonal SMN, with selective expression in the axons of spinal cord motor neurons, has been recently reported by our group. We intend to verify the in vivo function and therapeutic properties of the FL-SMN and a-SMN proteins in both invertebrate and mammalian experimental settings.

Generation of authentic human striatal neurons from pluripotent stem cells for transplantation in Huntington's disease
2013-January 2016 | PRIN - Italian Ministry of University and Research

Coordinator: Elena Cattaneo; Head of local research unit: Alessandro Vercelli
Research Network: Biella Gerardo Rosario, University of Pavia; Biunno Ida, Cnr; Moresco Rosa Maria, University Milano-Bicocca

The anatomy of the striatum in mammals is characterized by medium-sized spiny GABAergic projection neurons and by 5% interneurons. On immunohistochemical and histochemical grounds, the striatum can be subdivided in lightly labeled striosomes and an intensely labeled matrix, in which neurons are differentially organized. The striatum is part of neural circuits which play a role in motor behavior and in the mechanisms of reward. The anatomical organization is completely disrupted  in Huntington's disease, where projection neurons degenerate massively, causing a secondary neuronal death in the substantia nigra, to which the striatum is strongly interconnected.

The aim of the consortium is to explore the potential for a specific set of stem cells, human ventral striatal progenitors, derived from embryonic stem cells, to  replace lost projection neurons in a rat experimental model of Huntington's  disease.
In the frame of this project, UNITO will be responsible for studying the anatomical integration of stem cells in the striatum. The results obtained by our UNIT will be compared with those obtained in the same animals on motor behavior in order to correlate improvement in motor performance with the proper differentiation of stem cells and their integration into neural circuits.

Use of biomimetic scaffolds and stem cells to support the regeneration of the injured spinal cord
2014-2016 | Fondazione CRT

Marina Boido, NICO co-PI with Gianluca Ciardelli e Chiara Tonda-Turo, Politecnico di Torino

The project derives from a collaboration between UNITO and POLITO. In the project we employ hydrogels (biomimetic polyurethanes, water-soluble and heat-sensitive) in which stem cells (embryonic or adult) are encapsulated. The scaffolds are tested in vitro, in order to assess their ability to host the cells.
Moreover we aim to inject scaffolds and stem cells in vivo, in a mouse model of spinal cord contusion. To evaluate the efficacy of the treatment, we intend to study sensorimotor performance of animals, the survival/integration of cells in the host tissue, and the expression of molecules involved in the regeneration and neuroinflammation.

Amyloid-β accumulation: the role of Ubiquitin C-terminal hydrolase L1 (Uch-L1)
2015 | Grant Fondazione Veronesi - Michela Guglielmotto

Alzheimer’s disease (AD) is the most common age-related disorder that results in the loss of memory and cognitive functions. Accumulation of amyloid-β peptides (Aβ), the main components of senile plaques, in the brain represents the key pathological event of AD (Selkoe, 2001). Aβ results from two sequential endoproteolytic cleavages operated on the amyloid-β precursor protein (AβPP) by β-secretase (BACE1) and γ-secretase.

Oxidative stress together with important oxidative stress-related risk factors connected to AD such as hypoxia, hyperglycemia and hypercholesterolemia, are the potential causes of the increased BACE1 activity. Recently it has been demonstrated that the link between stroke, brain ischemia, and AD is hypoxia, the direct consequence of cerebral hypoperfusion. Indeed, hypoxia increases BACE1 expression and activity, resulting in Aβ overproduction, as it has been shown in vitro as well as in AD transgenic mice.

This project aims to expand the knowledge gathered by our previous results. We demonstrated that hypoxia, both in vitro and in vivo , up-regulates BACE1 mRNA expression in a biphasic manner. Also, we showed that Aβ1-42 down-regulates the activity of ubiquitin C-terminal hydrolase L1 (Uch-L1) and that this event is associated with BACE1 up-regulation owing to a transcriptional effect and to an impairment of its lysosomal degradation.
Uch-L1 is an abundant neuronal enzyme , involved in either the addition or the removal of ubiquitin from proteins that are destined to be metabolized via the ATP-dependent proteasome pathway.
On these bases, we aim to demonstrate:

  • if the Uch-L1 inhibition can be found in different models of brain injury related to AD pathogenesis such as hypoxic and ischemic injury and
  • if this decrease could be a mechanism leading to an up-regulation of BACE1 and a Aβ overproduction, with consequent neuronal cell death.