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.
The data presented in this article are related to the research paper entitled “Increased expression of mitochondrial sodium-coupled ascorbic acid transporter-2 (mitSVCT2) as a central feature in breast cancer”, available in Free Radical Biology and Medicine Journal [1]. In this article, we examined the SVCT2 transporter expression in various breast cancer cell lines using RT-PCR and Western blot assays. In addition, we analyzed the subcellular localization of SVCT2 by immunofluorescence colocalization assays and cellular fractionation experiments. Finally, an analysis of different cancer tissue microarrays immunostained for SVCT2 and imaged by The Human Protein Atlas (https://www.proteinatlas.org) is presented.
The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas (hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.
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