Synaptic Dysfunction
Nowadays it is assumed that AD is a synapse-related pathology leading to synaptic dysfunction and loss, a phenomenon that precedes extensive amyloid deposition in the brain. At the same time, soluble diffusible forms of Aβ can perturb in an early stage of the disease the synaptic function causing a reduction of dendritic spines density in the cortex and hippocampus, an acute inhibition of long term potentiation (LTP) and the loss of critical spine proteins (e.g. membrane expression of NMDA receptors).
However, the relationship between Aβ and synapses loss remains unclear and more efforts are necessary to better understand the mechanisms underlying Aβ synaptic toxicity.
Our aim is to study the effects of Aβ oligomers on MAPKs pathways and elucidate the link between synaptopathies and the activation/inhibition of the JNK, p38 and ERK cascades. This study can potentially be a breakthrough in the comprehension of AD pathogenesis: understanding the cellular and molecular alterations that lead to AD will help in developing effective and preventive therapeutic strategies in order to counteract or nullify the degenerative processes activated by Aβ.
MAPKs (ERK, p38 and JNK) are also implicated in the regulation of the immediate early signalling events that modulate synaptic plasticity by controlling LTP, LTD and the recycling of glutamate receptors (NMDAR and AMPAR) as well as their expression. Nevertheless, MAPKs involvement in the regulation of synaptic function and dysfunction and the mechanisms by which they trigger the synaptic loss induced by Aβ oligomers are largely unknown.