CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Neurodegeneration: building the bridge from neurobiology to treatment of brain disorders

Techniques - In vitro and in vivo electrophysiology, immunohistochemistry and confocal microscopy, primary cell cultures, immunoassays, animal behavior.

Our goals are:
i) to disclose the role of the cholinergic system and neurotrophins in synaptic plasticity and neurodegenerative diseases,
ii) to clarify the mechanisms underlying beta-amyloid (Aβ) toxicity,
iii) to protect neuronal cells in neurodegenerative diseases.

 

Role of cholinergic system and neurotrophins in synaptic transmission and plasticity: from physiology to pathology

Our results showed that acetylcholine (Ach) is able to change the functional dynamics of neocortical circuitry through activation of different subtypes of muscarinic receptors. In addition, since the cholinergic system is affected in AD, we studied the impact of cholinomimetic treatment on synaptic plasticity impairment in anti-NGF transgenic mice, a murine-type model for AD (Kuczewski et al., J physiol, 2005; Origlia et al., J Alzh Dis., 2006; Origlia et al., J Physiol, 2006)

 

 

 

 

Aβ synaptic dysfunction: the role of MAPKs

 

Alzheimer's disease (AD) is one of the main form of neurodegenerative disorders leading to cognitive impairment with dementia. Typical feature of AD is the presence of senile plaques formed by beta amyloid (Aβ) aggregates. At early stages of AD before plaques formation, Aβ is already present as soluble oligomeric form. We demonstrated for the first time that in the parahippocampal and neocortical areas, low level of soluble Aβ induces an alteration of Long Term Potentiation (LTP), a form of synaptic plasticity involved in learning and memory, through phosphorylation of different MAPKs such as P38 MAPK and/or JNK (Origlia et al., 2008; 2009)

 

 

Aβ synaptic dysfunction: the role of RAGE

 

Receptor for Advanced Glycation Endproducts (RAGE) is a surface receptor of IgG superfamily expressed in neurons, glial cells and microglia and functions as cell surface binding site for soluble Aβ peptides. To investigate intracellular pathway transducing RAGE activation by Aβ, we used inhibitors of stress activated kinases in slices and neuronal cell cultures.

We found that Aβ-induced enhancement of stress-MAPK phosphorylation is mediated by RAGE and contributes to synaptic dysfunction. The outcome of these studies is important to clarify the role of RAGE and Aβ in development of cortical neurodegenerative processes in AD. Deciphering new molecular aspect in AD pathology will open up the possibility to define new therapeutical strategies and new pharmacological treatments with a consequent high impact from social point of view (Origlia et al., 2008; Origlia et al., 2009a; b). This work is in collaboration with Prof. S.D. Yan and O. Arancio (Columbia University, New York).

Development, aging and repair of the retina: focus on BDNF

The retinal circuitry represents an interesting structure to investigate factors and mechanisms involved in aging (Valenzano et al., 2006; Terzibasi et al., 2009) and tissue repair. In particular, our interest is focused on the role of neurotrophic factors of NGF family (neurotrophins) and endogenous peptides in development and aging of mammalian retina. The role of BDNF and BDNF-like compounds in animal models of chronic glaucoma is actively investigated. This work is conducted in collaboration with Prof. A. Cellerino (Scuola Normale Superiore, Pisa, University of Jena), Prof. L. Giovannini (University of Pisa), Farmigea spa (Ospedaletto, Pisa, Italy).

Publications

  • Cellerino A, Maffei L, Domenici L (1996) The distribution of brain-derived neurotrophic factor and its receptor trkB in parvalbumin-containing neurons of the rat visual cortex. Eur. J. Neurosci. 8:1190-7.
  • Domenici L, Cellerino A, Maffei L (1993) Monocular deprivation effects in the rat visual cortex and lateral geniculate nucleus are prevented by nerve growth factor (NGF). II. Lateral geniculate nucleus. Proc. Biol. Sci. 251:25-31.
  • Origlia N, Arancio O, Domenici L, Yan SS (2009) MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE. Expert Rev Neurother 9:1635-45.
  • Domenici L, Berardi N, Carmignoto G, Vantini G, Maffei L (1991) Nerve growth factor prevents the amblyopic effects of monocular deprivation. Proc. Natl. Acad. Sci. U.S.A. 88:8811-5.
  • Origlia N, Capsoni S, Cattaneo A, Fang F, Arancio O, Yan SD, Domenici L (2009) Abeta-dependent Inhibition of LTP in different intracortical circuits of the visual cortex: the role of RAGE. J. Alzheimers Dis. 17:59-68.
  • Terzibasi E, Valenzano DR, Benedetti M, Roncaglia P, Cattaneo A, Domenici L, Cellerino A (2008) Large differences in aging phenotype between strains of the short-lived annual fish Nothobranchius furzeri. PLoS ONE 3:e3866.
  • Origlia N, Righi M, Capsoni S, Cattaneo A, Fang F, Stern DM, Chen JX, Schmidt AM, Arancio O, Yan SD, Domenici L (2008) Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. J. Neurosci. 28:3521-30.
  • Terzibasi E, Calamusa M, Novelli E, Domenici L, Strettoi E, Cellerino A (2009) Age-dependent remodelling of retinal circuitry. Neurobiol. Aging 30:819-28.
  • Origlia N, Kuczewski N, Aztiria E, Gautam D, Wess J, Domenici L (2006) Muscarinic acetylcholine receptor knockout mice show distinct synaptic plasticity impairments in the visual cortex. J. Physiol. (Lond.) 577:829-40.
  • Origlia N, Capsoni S, Domenici L, Cattaneo A (2006) Time window in cholinomimetic ability to rescue long-term potentiation in neurodegenerating anti-nerve growth factor mice. J. Alzheimers Dis. 9:59-68.
  • Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr. Biol. 16:296-300.
  • Kuczewski N, Aztiria E, Gautam D, Wess J, Domenici L (2005) Acetylcholine modulates cortical synaptic transmission via different muscarinic receptors, as studied with receptor knockout mice. J. Physiol. (Lond.) 566:907-19.
  • Pattabiraman PP, Tropea D, Chiaruttini C, Tongiorgi E, Cattaneo A, Domenici L (2005) Neuronal activity regulates the developmental expression and subcellular localization of cortical BDNF mRNA isoforms in vivo. Mol. Cell. Neurosci. 28:556-70.
  • Brancucci A, Kuczewski N, Covaceuszach S, Cattaneo A, Domenici L (2004) Nerve growth factor favours long-term depression over long-term potentiation in layer II-III neurones of rat visual cortex. J. Physiol. (Lond.) 559:497-506.
  • Domenici L, Parisi V, Maffei L (1992) Exogenous supply of nerve growth factor prevents the effects of strabismus in the rat. Neuroscience 51:19-24.
  • Maffei L, Berardi N, Domenici L, Parisi V, Pizzorusso T (1992) Nerve growth factor (NGF) prevents the shift in ocular dominance distribution of visual cortical neurons in monocularly deprived rats. J. Neurosci. 12:4651-62.
  • Pesavento E, Margotti E, Righi M, Cattaneo A, Domenici L (2000) Blocking the NGF-TrkA interaction rescues the developmental loss of LTP in the rat visual cortex: role of the cholinergic system. Neuron 25:165-75.

Collaborations

  • Alberto Auricchio e Enrico Surace, TIGEM, Napoli.
  • Paola Bagnoli, Dipartimento di Biologia, Università di Pisa.
  • Silvia Bisti, Dipartimento STB dell'Università dell'Aquila.
  • Antonino Cattaneo, EBRI-Roma e SNS-Pisa.
  • Alessandro Cellerino, Scuola Normale Superiore di Pisa; University of Jena, Germany.
  • Luca Giovannini, Dipartimento di Neuroscienze dell'Università di Pisa.
  • Giuseppe Lembo, Università La Sapienza Roma; NEUROMED, Pozzilli (Is).
  • Ferdinando Sartucci, Dipartimento di Neuroscienze dell'Università di Pisa.
  • Armando Piccinni, Unità Ospedaliera di Psichiatria, Ospedale Santa Chiara, Pisa.
  • Alessandro Rossi, Dipartimento di Scienze Neurologiche e del Comportamento, Università di Siena.
  • Jurgen Wess, NIH, Bethesda, USA.
  • Shi-Du Yan e Ottavio Arancio, Columbia University NY, USA.

 

PI photo

Luciano Domenici

Contact information

email  E-mail

email  +39 050 3153182

Participating staff

Chiara Criscuolo
PhD student

Linda Adzovic
PhD student

Elisa Cerri
Lab technician

Davide Barloscio
Lab Technician