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.

Carlos Alberto Castillo,José Luis Albasanz,David Agustín León-Navarro,Inmaculada Ballesteros-Yáñez,Mairena Martín

doi:10.3390/ijms22126577

Carlos Alberto Castillo, José Luis Albasanz + Show 3 more

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https://doi.org/10.3390/ijms22126577

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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.

Highlights

Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive functions, and the accumulation of amyloid β (Aβ) peptide in senile plaques is one of the main hallmarks in AD [1]
It has been assumed for decades that amyloid precursor protein (APP) has a prominent role in memory acquisition that could be mediated by Aβ peptide [2], but it has been believed that Aβ1-42 peptide is synaptotoxic per se in the absence of plaque burdens [3]
We introduced Aβ1-42 (25 μM, 24 h) as a positive control to compare with the effects of the whole peptide form of Aβ (Figure 1, panel B)

Summary

Introduction

Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive functions, and the accumulation of amyloid β (Aβ) peptide (such as Aβ1-42) in senile plaques is one of the main hallmarks in AD [1]. It has been assumed for decades that APP has a prominent role in memory acquisition that could be mediated by Aβ peptide [2], but it has been believed that Aβ1-42 peptide is synaptotoxic per se in the absence of plaque burdens [3] In this sense, it has been known for a long time that the physiological production of soluble Aβ1-40 peptide is a crucial factor for the maintenance of neurons viability [4]; even some authors propose that soluble purified monomers Aβ1-42 peptide may have a neuroprotective role [5,6]. Aβ25-35 has often been chosen as a model in structural and functional studies, which has contributed to the understanding of the effects of Aβ-mediated toxicity and has facilitated the study of the modulation of its toxicity [11]

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