P2X receptor overexpression induced by soluble oligomers of amyloid beta peptide potentiates synaptic failure and neuronal dyshomeostasis in cellular models of Alzheimer's disease

Abstract

The most common cause of dementia is Alzheimer's disease. The etiology of the disease is unknown, although considerable evidence suggests a critical role for the soluble oligomers of amyloid beta peptide (Aβ). Because Aβ increases the expression of purinergic receptors (P2XRs) in vitro and in vivo, we studied the functional correlation between long-term exposure to Aβ and the ability of P2XRs to modulate network synaptic tone. We used electrophysiological recordings and Ca microfluorimetry to assess the effects of chronic exposure (24 h) to Aβ oligomers (0.5 μM) together with known inhibitors of P2XRs, such as PPADS and apyrase on synaptic function. Changes in the expression of P2XR were quantified using RT-qPCR. We observed changes in the expression of P2X1R, P2X7R and an increase in P2X2R; and also in protein levels in PC12 cells (143%) and hippocampal neurons (120%) with Aβ. In parallel, the reduction on the frequency and amplitude of mEPSCs (72% and 35%, respectively) were prevented by P2XR inhibition using a low PPADS concentration. Additionally, the current amplitude and intracellular Ca signals evoked by extracellular ATP were increased (70% and 75%, respectively), suggesting an over activation of purinergic neurotransmission in cells pre-treated with Aβ. Taken together, our findings suggest that Aβ disrupts the main components of synaptic transmission at both pre- and post-synaptic sites, and induces changes in the expression of key P2XRs, especially P2X2R; changing the neuromodulator function of the purinergic tone that could involve the P2X2R as a key factor for cytotoxic mechanisms. These results identify novel targets for the treatment of dementia and other diseases characterized by increased purinergic transmission.

Exploring the Role of P2X Receptors in Alzheimer’s Disease

“…Chronic exposure to Aβ decreased SV2 and PSD95 proteins and this effect was prevented by PPADS, a P2XR antagonist. Furthermore, PPADS was able to prevent the decrease in cell viability observed with Aβ (Sáez-Orellana et al, 2018). Using qRT-PCR, a significant increase in mRNA for P2X1, 2, 5, and 7 was found after 12 h of exposure to Aβ, but after 24 h only P2X2 remained increased (Sáez-Orellana et al, 2018).…”

“…ATP can generate calcium transients in glial cells, and it appears to contribute to astrocytic hyperactivity in a mouse AD model (Delekate et al, 2014). Therefore, some authors have proposed that ATP participates in the inflammation process widely described in this neurodegenerative disease (Heppner et al, 2015; McGeer et al, 2016), while others propose that ATP, through some P2X receptors (P2XR), could participate directly in some of the toxic SOAβ effects observed in neurons (Sáez-Orellana et al, 2016; Sáez-Orellana et al, 2018).…”

Age-associated decline in Nrf2 signaling and associated mtDNA damage may be involved in the degeneration of the auditory cortex: Implications for central presbycusis

“…The PC12 rat pheochromocytoma cell line, a traditional cell line for neuroscience studies, is commonly used in neurobiology and neuropharmacology in vitro ( 48 , 49 ). In addition, the PC12 cell line has been widely used as a model to investigate oxidative stress-induced cell injury and senescence ( 50 - 52 ).…”

The purinergic P2X7 receptor as a potential drug target to combat neuroinflammation in neurodegenerative diseases

“…156 A more recent study showed that P2X7R overexpression induced by Aβ oligomers, augmented synaptic failure and neuronal dyshomeostasis in cellular models of AD. 157 In addition, a paradoxical neuroprotective effect of P2X7R stimulation has been reported. 153 Moreover, P2X7R…”