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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    • "Ab 1–42 fibrils were prepared as detailed in the Supplementary Data and as previously described[27]. After incubation at 37 C for 7 days, the mixture of Ab species was centrifuged for 10 minutes at 15,000 g, room temperature, the supernatant was discarded and the pellet, enriched in Ab fibrils, was resuspended in HAM's F12 buffer (pH 7.5) at a final concentration of 50 mM. "
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    ABSTRACT: Mononuclear phagocytes play a critical role during Alzheimer's disease (AD) pathogenesis due to their contribution to innate immune responses and amyloid beta (Aβ) clearance mechanisms.
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    • "Research on apoptosis of neural cells in AD is key for determining the relative toxicity of intracellular versus extracellular Aβ as well as of Aβ oligomers versus insoluble fibers (Resende et al., 2008). Apoptosis has been reported as a major cause of cell death in AD (Su et al., 1994). "
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    ABSTRACT: Crocin, as a carotenoid, is one of the main and active constituents of saffron stigmas (Crocus sativus L.) that is widely used in folk medicine. Several studies have pointed out the potent antioxidant and neuroprotective properties of crocin which may have therapeutic values for management of neurodegenerative disorders such as Alzheimer's disease. Alzheimer's disease is the most common form of dementia among the elderly and is characterized by massive neuronal loss and progressive cognitive impairment. Beta amyloid hypothesis is the main theoretical research framework for Alzheimer's disease which states that extracellular aggregation of beta amyloid results in synaptic loss and eventually cell apoptosis. Recent findings suggest that autophagy and apoptosis are extensively involved in Alzheimer's disease. In order to investigate therapeutic values of crocin, we examined the effect of crocin on memory, cell apoptosis, and autophagy using in vivo models of Alzheimer's disease. We also compared the effect of crocin administration on spatial memory with nicotine as positive control. Morris water maze results show that intra-peritoneal and intra-hippocampal administration of crocin significantly improve spatial memory indicators such as escape latency, traveled distance and time spent in target quadrant when compared to beta amyloid injection. Furthermore, we measured certain biomarkers of cell autophagy and apoptosis using Western blot analysis. Our results reveal that crocin administration does not cause any significant alteration in Beclin-1 and ratio of LC3-II/LC3-I compared to the group received beta amyloid by hippocampal injection. However, in contrast to autophagy, crocin administration significantly decreases Bax/Bcl-2 ratio and cleaved Caspase-3 level. This demonstrates that crocin inhibits beta amyloid induced apoptosis, which is possibly associated with its antioxidant properties. Our results further confirm the neuroprotective properties of crocin as a potential pharmaceutical agent for management of Alzheimer's disease.
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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.
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