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Synaptic alterations and synaptotoxicity due to Amyloid beta oligomers

Mardi 26 janvier 2016 13:00 - Duree : 1 heure
Lieu : Amphithéâtre Serge Kampf, Grenoble Institut des Neurosciences (GIN) - Bât. Edmond J. Safra, Chemin Fortune Ferrini CHU, La Tronche

Orateur : José MARTINEZ-HERNANDEZ (Equipe Andrieux)

Alzheimer’s disease (AD) is a chronic neurodegenerative disease that usually starts slowly and gets worse over time. It accounts for 60% to 70% of cases of dementia. Gradually, bodily functions are lost, ultimately leading to death. The disease process is associated with amyloid plaques (deposits of Aβ peptide) and neurofibrillary tangles (containing the Tau protein) in the brain. Since soluble amyloid-β oligomers (Aβo) are able to affect the Tau distribution and translocate Tau into dendritic spines, Aβo could induce synapse dysfunction and loss in the early phase of the disease, which would provide the best correlate to cognitive impairment, rather than amyloid plaque load in a late state of the disease. In primary cortical cultures, we applied Aβo (100nM) in the medium and were able to detect Aβo inside the neurons after a short incubation period (15 min), using immunolabeling and electron microscopy. To mimic the early phase of the disease and observe how the spine cytoskeleton is affected, we applied Aβo to the neurons in culture and measured the actin dynamics in the dendritic spines (using FRAP, Fluorescence Recovery After Photobleaching). Aβo increased the pool of stable actin. Transfecting the neurons with a calcium probe (GCAMP6F), we monitored the neuron activity and observed that this activity was reduced by Aβo exposition. Both of these effects could be reversed by Fasudil, a Rho-Kinase inhibitor. Down-stream to Rho-kinase, there is Cofilin1, a protein that severs the actin filaments, thereby increasing their turn over. A biochemical analysis of the PSD-enriched fraction of cultured neurons treated with Aβo, of APP/PS-1 mouse brain, or of AD human brain samples showed an increase of phosphorylated Cofilin1, the inactive form of the protein. Transfecting the neurons with constitutively active/inactive versions of Cofilin, both actin dynamics and the neurons activity became insensitive to the Aβo treatment. Finally, we observed that a longer exposition period (24h) produced the disappearance of dendritic spines. Thus Aβo affects synaptic plasticity after a short exposure and causes synaptotoxicity following longer expositions.

Contact : yves.goldberg@ujf-grenoble.fr

Discipline évènement : (Biologie / Chimie)
Entité organisatrice : (GIN)
Nature évènement : (Séminaire)
Site de l'évènement : Pôle Santé / La Tronche

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