Dissection of Aβ oligomer synaptotoxic signaling in human neocortical neurons

Research team: Maria Teresa Dell’Anno, Francesco Olimpico

Alzheimer’s disease (AD) is one of the most common cause of senile dementia. The cognitive impairement, typical of the disease, has a drastic impact on the lives of patients and has a progressive evolution which ultimately leads to death. The severity of symptoms has been correlated with amyloid β oligomers (Aβo) levels in the brain. Aβo bind to the cellular prion protein (PrPC) and through the metabotropic glutamate receptor 5 (mGluR5) trigger the activation of an intracellular pathway culminating in excitotoxicity and synapse loss. The identification of the molecular events evoked by Aβo has opened the way to the experimentation of new pharmacological tools. However, the validation of the PrPC-mGluR5 pathway has never been performed on human neurons.

The neocortex is strongly affected in AD and the availability of human neocortical (NCX) neurons from iPS cells is relevant for disease modeling. While extensive literature has demonstrated that iPS cells can be efficiently generated from AD patients, the trascriptional profile of iPS derived- neurons has never been systematically compared with real human NCX-cells.

Here, I propose to run a comparative study to analyze the cellular response to Aβo using NCX-neurons obtained from two sources: human neocortical neuroepithelial stem (NCX-NES) cells from developing brains and from sporadic AD patient iPS cells. Using these two cell sources I aim to demonstrate for the first time the activation of PrPC-mGluR5 pathway in human NCX-neurons and to validate the quality of cell reprogramming and neuronal generation starting from sporadic AD patient somatic cells.