Resende de Oliveira C. Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1-42: involvement of endoplasmic reticulum calcium release in oligomer-induced cell death

Institute of Biochemistry, Faculty of Medicine and Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Neuroscience (Impact Factor: 3.36). 07/2008; 155(3):725-37. DOI: 10.1016/j.neuroscience.2008.06.036
Source: PubMed


The nature of the toxic form of amyloid-beta peptide (Abeta) involved in early Alzheimer's disease (AD) pathology and whether it is the fibrillar or the oligomeric peptide that is the most deleterious to neurons remain controversial. This work aimed to compare the neurotoxicity of different amyloid-beta peptide 1-42 (Abeta1-42) assemblies, using fresh and aged samples enriched in oligomeric and fibrillar species, respectively, and also isolated oligomers and fibrils. The results obtained with fresh and aged Abeta1-42 preparations suggested that oligomeric species are more toxic to cortical neurons in culture than fibrillar forms, which was confirmed by using isolated oligomers and fibrils. In order to further elucidate the mechanisms involved in soluble Abeta toxicity, the involvement of endoplasmic reticulum (ER) calcium (Ca(2+)) release in oligomer-induced apoptosis was evaluated. We observed that oligomeric Abeta1-42 depletes ER Ca(2+) levels leading to intracellular Ca(2+) dyshomeostasis involving phospholipase C activation. Moreover, in the presence of dantrolene, an inhibitor of ER Ca(2+) release through ryanodine receptors, the oligomer-induced apoptosis was prevented demonstrating the involvement of ER Ca(2+) release.

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    • "Changes in cytosolic calcium levels were determined using Indo-1/AM as fluorescent cationic dye, using a previously described procedure (Resende et al., 2008). After treatment, cells seeded in 48 well plates were incubated in 0.3 ml Krebs medium supplemented with 3 mM Indo-1/AM for 45 min at 37 C, protected from light. "
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    ABSTRACT: Context: Foliol, linearol, and sidol are the most common diterpenes found in Sideritis L. spp. (Lamiaceae) with a wide range of demonstrated properties including anti-inflammatory, antioxidant, and anti-apoptotic effects. Objective: For the first time, the present work was studied for the potential protective role of these kaurane-type diterpenes on mitochondrial oxidative stress induced by H2O2 in the human astrocytoma U373-MG cell line and in the rat adrenal pheochromocytoma PC12 cell line. Materials and methods: Mitochondrial protection was assayed at 5 and 10 µM concentrations for 24 h (for kaurane diterpenes) and H2O2 as oxidative stress inducer (0.1 mM for PC12 cells and 1 mM for U373-MG, for 30 min). ATP concentration was determined by high-performance liquid chromatography (HPLC), and changes in mitochondrial membrane potential, caspase-3 activity as well as in cytosolic and mitochondrial calcium levels were assessed by fluorometric techniques, by using specific fluorescent probes. Results: Pretreatments for 24 h with linearol and sidol, prior to H2O2 exposure, acted as mitochondrial alterations preventive agents by increasing membrane potential (over 40-60% in PC12 cells and over 10-20% in U373-MG), restoring both cytosolic and mitochondrial calcium homeostasis (linearol at 10 µM caused a 3.5-fold decrease in cytosolic calcium concentration in PC12 cells), decreasing caspase-3 activity (over 1.25-1.5-fold for linearol and sidol) and avoiding ATP depletion (linearol increased over 20% ATP level in both cell types). Conclusion: Our results suggest that linearol and sidol could provide protective activity by targeting mitochondria in response to the deleterious changes induced by H2O2.
    Pharmaceutical Biology 10/2015; DOI:10.3109/13880209.2015.1072829 · 1.24 Impact Factor
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    • "Moreover, a positive correlation between brain levels of the ER chaperone GRP78 and Braak staging was shown in AD patients [5] [116]. Aβ is strongly implicated in AD pathogenesis and is also linked to ER stress [118]. Cultured neurons exposed to Aβ present increased levels of GRP78 [119]. "
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    ABSTRACT: Neurodegenerative disorders such as Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected. In these pathologies, several evidences support a close correlation between neurodegeneration and endoplasmic reticulum (ER) stress, a condition that arises from ER lumen overload with misfolded proteins. Under these conditions, ER stress sensors initiate the unfolded protein response to restore normal ER function. If stress is too prolonged, or adaptive responses fail, apoptotic cell death ensues. Therefore, it was recently suggested that the manipulation of the ER unfolded protein response could be an effective strategy to avoid neuronal loss in neurodegenerative disorders. We will review the mechanisms underlying ER stress-associated neurodegeneration and discuss the possibility of ER as a therapeutic target.
    CNS & neurological disorders drug targets 04/2015; 14(4). DOI:10.2174/1871527314666150429112353 · 2.63 Impact Factor
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    • "Importantly, these mice also exhibit amyloid angiopathy followed by weakened vessel walls, aneurysm, vasculitis, and haemorrhage [27] [28]. Numerous in vitro studies demonstrate the synaptic and neuronal toxicity induced by Aβ including, but not limited to: evidence of abnormal tau phosphorylation, Ca 2+ deregulation, oxidative stress, mitochondrial and endoplasmic reticulum (ER) dysfunction, neuroinflammation, alteration of synaptic transmission, excitotoxicity, changes in membrane cholesterol levels and distribution, and activation of cell death pathways [18] [29] [30] [31] [32] [33] [34] [35]. "
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    ABSTRACT: Alzheimer’s disease (AD) is the principal cause of dementia in the elderly; however, its prevalence is increasing due to the fact that current pharmaceuticals used to manage the symptoms are not capable of preventing, halting, or reversing disease progression. In the last decade, evidence has accumulated to support the hypothesis that a primary cerebral vascular dysfunction initiates the cascade of events that leads to neuronal injury and the subsequent cognitive decline observed in AD. The mechanisms underlying these vascular defects and their relationship with neurodegeneration are still poorly understood however. It is pathologically known that cerebrovascular dysfunctions can induce the deposition of amyloid-β (Aβ), an amyloidogenic and toxic peptide that in turn causes cerebrovascular degeneration. Mammalian cells regulate proteostasis and the functioning of intracellular organelles through diverse mechanisms such as the Unfolded Protein Response, the Ubiquitin-Proteasome System and autophagy; however, when these mechanisms cannot compensate for perturbations in homeostasis, the cell undergoes programmed death via apoptosis. This review summarizes recent studies that together correlate the deregulation of protein quality control pathways with dysfunction of vascular endothelial cells of the brain in AD, thus supporting the hypothesis that it is the vicious, progressive failure of the proteostatic network and endothelial activation that underlies the cerebrovascular changes that symptomize AD.
    01/2015; 2(1). DOI:10.1515/ersc-2015-0005
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