Early Effects of the Soluble Amyloid β(25-35) Peptide in Rat Cortical Neurons: Modulation of Signal Transduction Mediated by Adenosine and Group I Metabotropic Glutamate Receptors

The amyloid β peptide (Aβ) is a central player in the neuropathology of Alzheimer’s disease (AD). The alteration of Aβ homeostasis may impact the fine-tuning of cell signaling from the very beginning of the disease, when amyloid plaque is not deposited yet. For this reason, primary culture of rat cortical neurons was exposed to Aβ(25-35), a non-oligomerizable form of Aβ. Cell viability, metabotropic glutamate receptors (mGluR) and adenosine receptors (AR) expression and signalling were assessed. Aβ(25-35) increased mGluR density and affinity, mainly due to a higher gene expression and protein presence of Group I mGluR (mGluR(1) and mGluR(5)) in the membrane of cortical neurons. Intriguingly, the main effector of group I mGluR, the phospholipase C β(1) isoform, was less responsive. Also, the inhibitory action of group II and group III mGluR on adenylate cyclase (AC) activity was unaltered or increased, respectively. Interestingly, pre-treatment of cortical neurons with an antagonist of group I mGluR reduced the Aβ(25-35)-induced cell death. Besides, Aβ(25-35) increased the density of A(1)R and A(2A)R, along with an increase in their gene expression. However, while A(1)R-mediated AC inhibition was increased, the A(2A)R-mediated stimulation of AC remained unchanged. Therefore, one of the early events that takes place after Aβ(25-35) exposure is the up-regulation of adenosine A(1)R, A(2A)R, and group I mGluR, and the different impacts on their corresponding signaling pathways. These results emphasize the importance of deciphering the early events and the possible involvement of metabotropic glutamate and adenosine receptors in AD physiopathology.