CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Synaptic dysfunction in animal models of neurodegeneration

Overview

The main focus of the lab is to investigate factors and mechanisms regulating synaptic transmission and plasticity either under physiological conditions or in animal models of neurodegeneration.

Current Research

Aβ induced synaptic dysfunction

 

Alzheimer's disease (AD) is one of the most common and severe form of progressive neurodegenerative disorders leading to cognitive impairment and dementia. A typical neuropathological feature of AD is the presence of β-amyloid deposits with the formation of plaques in different brain areas. Recent studies in AD animal models and affected patients highlighted the apparent discrepancy between neuropathological findings and cognitive impairments, providing evidence that loss of neuronal function and behavioral deficits precede the accumulation of beta amyloid containing plaques. Thus, the idea has been raised that neuronal dysfunction and cognitive decline during an early stage of AD is due to beta amyloid action in soluble oligomeric form. We demonstrated that in the parahippocampal and neocortical areas nanomolar concentrations of Aβ oligomers interfere with long term potentiation (LTP; Origlia et al., 2008; 2009). In addition, Aβ in the micromolar range of concentrations induces synaptic depression and long-term depression (LTD) impairment by regulating glutamate receptors function (Origlia et.al 2009; 2010, figure 1). These results support the concept that impaired LTP characterizes an early stage in AD progression corresponding to lower Aβ levels, while later stages are associated with a greater Aβ load that exaggerates impairments in basal synaptic transmission and LTD. Thus, progression of synaptic dysfunction by Aβ is concentration dependent, possibly corresponding to cognitive decline induced by its accumulation during AD.

Role of microglial and neuronal RAGE in Aβ mediated cortical synaptic dysfunction.

Receptor for Advanced Glycation Endproducts (RAGE) functions as cell surface binding site for Aβ. We investigated the role of cell-specific activation of RAGE (microglial vs. neuronal) in Aβ-dependent synaptic dysfunction using inhibitory antibodies to RAGE, RAGE knock-out mice(RAGEKO) and mice expressing a defective form of RAGE targeted to neurons (DN-RAGE) or microglia (DNMSR). We found that nanomolar Aβ impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK. Remarkably, accumulation of Aβ causes the activation of microglia and release of proinflammatory cytokines. We raised the key question of whether brain neuroinflammation is involved in progressive synaptic and cognitive deficits induced by Aβ load. Increasing Aβ concentration up to 1µM induces specific phosphorylation of p38 MAPK and JNK in neuronal and non-neuronal cells that depend on microglial RAGE activation along with the induction of proinflammatory cytokine, such as IL-1β. Interleukin-1β would consequently affect basal synaptic transmission and LTD (Origlia et al., 2010).
Our data suggest that the effect of increasing Aβ levels involves the activation of an inflammatory pathway establishing a self-maintained neuronal-microglial loop leading to synaptic dysfunction. (Figure 2)

 

A new molecular link between vascular pathology and Alzheimer’s Disease

Hypoxic condition may be the cause of progressive neuronal alterations in Alzheimer’s disease (AD). However, a causal relationship between oxygen deficiency and AD at the cellular and molecular level has not been established. Recent understanding has confirmed that RAGE plays a role in the pathogenesis of neurodegenerative disorders, including AD. Moreover, RAGE is up regulated in response to brain hypoxia/ischemia and its activation contributes to inflammation and ischemic brain damage. In this project we address the hypothesis that transient ischemia facilitates brain impairment induced by Aβ signaling through RAGE. We suggest that transient brain hypoxia/ischemia may function as a trigger for neuronal perturbation induced by progressive accumulation of Aβ and that RAGE could be an important factor in accelerating synaptic dysfunction in vascular pathology and AD.

Publications

  • Maya-Vetencourt JF, Origlia N (2012) Visual cortex plasticity: a complex interplay of genetic and environmental influences. Neural Plast. 2012:631965.
  • Piccinni A, Origlia N, Veltri A, Vizzaccaro C, Marazziti D, Catena-Dell'osso M, Conversano C, Moroni I, Domenici L, Dell'osso L (2012) Plasma ?-amyloid peptides levels: a pilot study in bipolar depressed patients. J Affect Disord 138:160-4.
  • Origlia N, Valenzano DR, Moretti M, Gotti C, Domenici L (2012) Visual acuity is reduced in alpha 7 nicotinic receptor knockout mice. Invest. Ophthalmol. Vis. Sci. 53:1211-8.
  • Origlia N, Bonadonna C, Rosellini A, Leznik E, Arancio O, Yan SS, Domenici L (2010) Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex. J. Neurosci. 30:11414-25.
  • Spalloni A, Origlia N, Sgobio C, Trabalza A, Nutini M, Berretta N, Bernardi G, Domenici L, Ammassari-Teule M, Longone P (2011) Postsynaptic alteration of NR2A subunit and defective autophosphorylation of alphaCaMKII at threonine-286 contribute to abnormal plasticity and morphology of upper motor neurons in presymptomatic SOD1G93A mice, a murine model for amyotrophic lateral sclerosis. Cereb. Cortex 21:796-805.
  • 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.
  • 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.
  • 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.
  • 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.

Grants

Alzheimer’s Association- New Investigator Research Grant (NIRG 10-173407)- “Role of microglial and neuronal RAGE in Aβ mediated synaptic dysfunction”.

Regione Toscana Regional Health program grant- “From brain ischemia to beta-amyloid toxicity”.

Collaborations

  • Shi-Du Yan, University of Kansas, Lawrence, KS.
  • Ottavio Arancio, Columbia University NY, USA.
  • Nicola Berretta, Fondazione S.Lucia, Rome.
  • Ferdinando Sartucci, Dipartimento di Neuroscienze dell'Università di Pisa.
  • Antonino Cattaneo, SNS -Pisa.
  • Armando Piccinni, Department of Psychiatry, University of Pisa, Pisa, Italy.

 

PI photo

Nicola Origlia

Contact information

email  E-mail

email  050 3153193

Participating staff
[--]