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Neuronal firing in early symptomatic Alzheimer's disease cell models

Docente
Prof. Valentina CARABELLI
Prof. Emilio CARBONE
Coordinatore/trice
Dott. Andrea MARCANTONI

Aree / Gruppi di ricerca

Partecipanti al progetto

Descrizione del progetto

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Members of other units:

Marie Hélène (Institute of Molecular and Cellular Pharmacology, Valbonne, France)

Partners:
CNRS, Université de Nice Sophia Antipolis, Valbonne, France 

Sponsors:
PRES Euro-Mediterraneo (University of Torino)

Description

Alzheimer’s disease (AD) is the most common cause of progressive dementia in aging human populations, and one of the most important medical, social and economic problems confronting contemporary society. It is characterized by progressive disturbances of cognitive functions including memory, judgment, decision-making, orientation to physical surroundings and language.

AD is characterized by several cellular hallmarks that primarily affect memory encoding brain regions such as the hippocampus and the neocortex [1]. These hallmarks consist of 1) progressive accumulation of oligomers of β-amyloid peptide (Aβ), produced by the proteolytic processing of the amyloid precursor protein (APP); 2) progressive accumulation of neurofibrillary tangles mainly composed of hyperphosphorylated tau; 3) death of basal forebrain cholinergic neurons projecting to the two memory-encoding structures; 4) synaptic degeneration. How these alterations relate to each other and which of them drive memory loss characteristic of AD is still unclear.

Considering the “amyloid-cascade hypothesis” (hallmark 1), it posits that the accumulation of Aβ into oligomers is the initiating event that triggers the progressive dismantling of the synapses, neuronal circuits and networks [2]. A possible mechanism of action still not completely understood consider Aβ able to induce “calcium dysregulation” phenomena [3] and alter both excitability and synaptic functions. In fact, the process of calcium entering into neurons through calcium channels is considered critical for governing both action potential generation [4] and neurotransmitter release [5]. In this project, new methodological approaches are proposed aiming at identifying the first neural impairment occurring  at the early stage of AD. Particular attention is given not only to the study of the hippocampus necessary for the consolidation of information from short-term to long-term memory and spatial navigation, but also to the main source of afferent input to the hippocampus represented by the enthorinal cortex (EC) and considered one of the first brain regions impaired during the early stages of AD.

In this context, the project aims at investigating the role exerted by calcium channels during the development of AD. By focusing on EC and hippocampus derived neurons the alterations of the main pathways of calcium entry and calcium release will be studied. The results obtained will provide key information regarding the modification of calcium homeostasis during the early phase of beta-amyloid (Ab) accumulation and new pharmacological therapies aiming to treat the development of Alzheimer’s disease will be proposed.

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References:
- Blennow K. et al. Lancet. 2006 368(9533):387-403
- Selkoe DJ. Science. 2002 298(5594):789-91
- Yu JT, Chang RC, Tan L. Prog Neurobiol. 
2009 Nov;89(3):240-55
- Marcantoni A, et al. J Neurosci. 2010 13;30(2):491-504
- Evans RM, Zamponi GW. Trends Neurosci. 2006 Nov;29(11):617-24

Keywords:
Alzheimer’s disease, Beta-amyloids, Calcium signals, Entorinhal cortex, Hippocampus, Neuronal excitability, Memory, Therapeutic drugs, Calcium channel modulators

Links:
bloggaTO - Informazioni e attualità del partenariato 
"P.R.E.S." Euro-Méditerranéen 

Ultimo aggiornamento: 17/07/2017 11:24
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