Early Effects of the Soluble Amyloid β25-35 Peptide in Rat Cortical Neurons: Modulation of Signal Transduction Mediated by Adenosine and Group I Metabotropic Glutamate Receptors

Abstract

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 Aβ25-35, a non-oligomerizable form of Aβ. Cell viability, metabotropic glutamate receptors (mGluR) and adenosine receptors (AR) expression and signalling were assessed. Aβ25-35 increased mGluR density and affinity, mainly due to a higher gene expression and protein presence of Group I mGluR (mGluR1 and mGluR5) in the membrane of cortical neurons. Intriguingly, the main effector of group I mGluR, the phospholipase C β1 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 Aβ25-35-induced cell death. Besides, Aβ25-35 increased the density of A1R and A2AR, along with an increase in their gene expression. However, while A1R-mediated AC inhibition was increased, the A2AR-mediated stimulation of AC remained unchanged. Therefore, one of the early events that takes place after Aβ25-35 exposure is the up-regulation of adenosine A1R, A2AR, 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.

Adenosine receptor signalling in Alzheimer’s disease

“…Animal and cellular models recapitulate these changes to AR expression, with increased A 1 R immunoreactivity in neurons with NFTs and in amyloid plaques, alongside enhanced glial A 2A R expression [201]. In human neuroblastoma cells and primary rat cortical neurons, administration of Aβ 25-35 increased A 1 R and A 1 R/A 2A R expression, respectively [209,210]. APP/PS1 AD mice show increased A 1 R and A 2A R levels compared to non-transgenic mice, and rats with sporadic dementia also show elevated A 2A R levels [123,211,212].…”

A metabotropic glutamate receptor 3 (mGlu3R) isoform playing neurodegenerative roles in astrocytes is prematurely up‐regulated in an Alzheimerʼs model

“…Certainly, this hypothesis deserves further analysis. To the best of our knowledge, there are no precedents showing mGlu3R regulation by Aβ in CNS cells, with the exception of one recent report showing a decrease in the density of mGlu2/3R at the membrane surface of cell bodies of cortical cultured neurons after Aβ 25‐35 exposure (Castillo et al, 2021). We found that Aβ down‐regulates expression of both mGlu3R and mGlu3Δ4 rather than increasing mGlu3Δ4 levels, which discourages a cause‐effect relation between Aβ and exon 4 splicing.…”

The Anti-Aggregative Peptide KLVFF Mimics Aβ1-40 in the Modulation of Nicotinic Receptors: Implications for Peptide-Based Therapy

“…Strong evidence has extensively demonstrated that amyloid is important in LTP and memory consolidation [ 43 , 44 , 45 ]. The second point is that amyloid appears to be a wide-spectrum modulator, interfering with a plethora of targets [ 19 , 46 , 47 , 48 , 49 , 50 , 51 ]. Therefore, the ability to block only the derangement of this protein could be relevant to the success of the amyloid-based strategy.…”