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Alzheimer's Disease Research - Completed Award

Dr. Luciano Domenici

Luciano Domenici, M.D., Ph.D.

National Council of Research (C.N.R.)
Pisa, Italy

Title: RAGE, MAP kinases and Abeta induced synaptic dysfunction
Non-Technical Title: Role of RAGE in Alzheimer's disease

Duration: April 1, 2008 - March 31, 2010
Award Type: Pilot
Award Amount: $148,000


Summary:

Nerve signaling dysfunctions triggered by ABeta are central to AD progression. This study will lead to a better understanding of these processes, in particular, RAGE signaling. Results of this study will facilitate design of therapeutic agents that prevent or minimize the actions of ABeta on nerve signaling.

Details:


Alzheimer's disease (AD) is one of the main form of progressive neurodegenerative disorders leading to cognitive impairment with dementia. A typical feature of AD is the presence of beta amyloid (Aß) deposits in the form of plaques in different brain areas. Recent studies have higlighted the apparent discrepancy between neuropathological findings and cognitive impairment such as memory loss in AD. In the present project we raise the hypothesis that impairment of memory and neuronal dysfunction during an early phase of AD is due to oligomeric Aß, i.e. a step before the formation of plaques. In particular, for the first time, we aim to demonstrate that oligomeric Aß induces a nerve dysfunction in the entorhinal cortex, one of the brain areas affected in AD. The project will use a combination of electrophysiological and molecular approaches to show the mechanisms underlying oligomeric Aß induced neuronal dysfunction including the identification of receptors mediating Aß dysfunction. The outcome of these studies will be important to clarify the role of Aß and its receptors in different temporal phases of cortical neurodegenerative processes in AD. Deciphering new molecular aspects in AD pathology will be essential to define new therapeutical strategies leading to halt the progress of disease.

Publications:

Origlia N, Bonadonna C, Rosellini A, Leznik E, Arancio O, Yan SS, Domenici L. 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. 2010 Aug 25;30(34):11414-25. PubMed Icon Google Scholar Icon

Sartucci, F., et al. (2010) Dysfunction of the magnocellular stream in Alzheimer's disease evaluated by pattern electroretinograms and visual evoked potentials. Brain Res Bull., 2010 May 31;82(3-4):169-76. Epub 2010 Apr 10. PubMed Icon Google Scholar Icon

Origlia N, Capsoni S, Cattaneo A, Fang F, Arancio O, Yan SD, Domenici L. Abeta-dependent Inhibition of LTP in different intracortical circuits of the visual cortex: the role of RAGE. J Alzheimers Dis. 2009 May;17(1):59-68. PubMed Icon Google Scholar Icon

Origlia, N et al. (2009). Microglial RAGE dependent signal pathway drives ABeta- induced synaptic depression in entorhinal cortex. SFN meeting abstract 800.4 [conference abstract] Origlia, N., et al. (2009) MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE. Expert Rev Neurother 9, 1635-1645 PubMed Icon Google Scholar Icon

Origlia et al. (2009) Neuronal and microglial RAGE-dependent signal pathways involved in ABeta-induced synaptic dysfunction in enthorinal cortex. ICAD meeting abstract P4-231. [conference abstract]

Origlia, N., et al. (2008) ABeta induces entorhinal cortex synaptic dysfunction through RAGE-dependent signal pathway. SFN meeting abstract 409.11 [conference abstract]