No 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.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly afflicts the elderly population. Soluble oligomers (AbOs) has been implicated in AD pathogenesis: however, the molecular events underlying a role for Ab are not well understood. We studied the effects of AbOs on mitochondrial function and on key proteins that regulate mitochondrial dynamics and biogenesis in hippocampal neurons and PC-12 cells. We find that AbOs treatment caused a reduction in total Mfn1 after a 2 h exposure (42 ± 11%); while DRP1 increased at 1 and 2 h (205 ± 22% and 198 ± 27%, respectively), correlating to changes in mitochondrial morphology. We also observed that SIRT1 levels were reduced after acute and chronic AbOs treatment (68 ± 7% and 77 ± 6%, respectively); while PGC-1a levels were reduced with the same time treatments (68 ± 8% and 67 ± 7%, respectively). Interestingly, we found that chronic treatment with AbOs increased the levels of pSIRT1 (24 h: 157 ± 18%), and we observed changes in the PGC-1a and p-SIRT1 nucleus/cytosol ratio and SIRT1-PGC-1a interaction pattern after chronic exposure to AbOs. Our data suggest that AbOs induce important changes in the level and localization of mitochondrial proteins related with the loss of mitochondrial function that are mediated by a fast and sustained SIRT1/PGC-1a complex disruption promoting a "non-return point" to an irreversible synaptic failure and neuronal network disconnection.

No abstract

Several studies have pointed to soluble oligomers of beta amyloid peptide (SOAβ) as the principal neurotoxic agents responsible for the generation of synaptotoxic events that can explain the main symptoms of Alzheimer’s disease (AD). Among the toxic features associated with SOAβ, one of the most notorious is the formation of a non-selective pore-like structure in the plasma membrane, which may partly explain the overload of intracellular Ca2+. There is evidence that the pore causes leakage of key intracellular compounds, such as adenosine triphosphate (ATP), to the extracellular milieu. Extracellular ATP activates P2X receptors (P2XR), which are ligand-gated ion channels (LGICs) widely expressed in both neuron and glial cells and act as neuromodulators of synaptic activity by promoting Ca2+ entry and facilitating neurotransmitter release. There is abundant evidence correlating the overexpression of these receptors to neurodegenerative diseases, including AD, thus opening the possibility that P2XR could potentiate the toxic mechanisms induced by SOAβ and contribute to intracellular Ca2+ overload in neurons and other mechanisms related to glial activation and inflammation. In this review, we correlate scientific evidence related to the main toxic effects induced by SOAβ and those that are mediated by purinergic P2XR. The data suggest that these purinergic receptors participate in the deleterious cellular and molecular effects of SOAβ that lead to the pathogenesis of AD. This information sheds light on the participation of new components in SOAβ toxicity that could be interesting as pharmacological targets for the development of molecular or chemical compounds able to modulate them.