Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1-42: involvement of endoplasmic reticulum calcium release in oligomer-induced cell death.
ABSTRACT 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.
SourceAvailable from: Hiroshi Tanaka[Show abstract] [Hide abstract]
ABSTRACT: Amyloid-beta (Aβ) peptides, Aβ 1-42 (Aβ42) and Aβ43 in particular, cause neurotoxicity and cell death in the brain of Alzheimer's disease (AD) at higher concentrations. Carnosic acid (CA), a phenolic diterpene compound in the labiate herbs rosemary and sage, serves as an activator for neuroprotective and neurotrophic functions in brain cells. We investigated the effect of CA on apoptosis induced by Aβ42 or Aβ43 in cultured SH-SY5Y human neuroblastoma cells. Treatment of the cells with Aβ42 or Aβ43 (monomer, 10μM each) induced apoptosis, which was confirmed by the cleavage of poly-(ADP-ribose) polymerase (PARP) and apoptosis-inducing factor (AIF). Concurrently, the Aβ treatment induced the activation of caspase (Casp) cascades including an effector Casp (Casp3) and initiator Casps (Casp4, Casp8 and Casp9). Pretreatment of the cells with CA (10μM) partially attenuated the apoptosis induced by Aβ42 or Aβ43. CA pretreatment also reduced the cellular oligomers of Aβ42 and Aβ43. These results suggest that CA suppressed the activation of Casp cascades by reducing the intracellular oligomerization of exogenous Aβ42/43 monomer. The ingestion of an adequate amount of CA may have a potential in the prevention of Aβ-mediated diseases, particularly AD. Copyright © 2014. Published by Elsevier Ireland Ltd.Neuroscience Research 12/2014; DOI:10.1016/j.neures.2014.12.003 · 2.15 Impact Factor
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ABSTRACT: Background: Amyloid-β (Aβ)-oligomers are neurotoxic isoforms of Aβ and are a potential diagnostic biomarker for Alzheimer's disease (AD). Objectives: 1) Analyze the potential of Aβ-oligomer concentrations in cerebrospinal fluid (CSF) to diagnose and predict progression to AD in a large clinical study sample. 2) Monitor Aβ-oligomer concentrations over-time, both in early and advanced stages of AD. 3) Examine the relation between Aβ-oligomer levels in CSF and cognitive functioning. Methods: 24 non-demented, 61 mild cognitive impairment (MCI), and 64 AD patients who underwent lumbar puncture and cognitive testing at baseline and follow-up were selected from the memory clinic based Amsterdam Dementia Cohort. CSF samples were analyzed for standard AD-biomarkers and Aβ-oligomer levels using a validated in-house Aβ-oligomer specific enzyme-linked immunosorbent assay. Aβ-oligomer levels were analyzed as indicators of disease progression (follow-up AD diagnosis) and cognitive decline, respectively. Results: Patient groups did not differ in Aβ-oligomer concentrations at baseline or follow-up. Baseline CSF Aβ-oligomer levels were similar in MCI patients that develop AD as in stable MCI patients. MCI and AD patients showed an annual decrease in Aβ-oligomer levels of 9.4% and 6.8%, respectively. A decrease in Aβ-oligomer levels over time was strongly associated with more severe cognitive decline in AD patients. Conclusion: Despite the limited diagnostic potential of Aβ-oligomer levels in CSF to differentiate between patient groups, and between MCI-AD and MCI-stable patients, changes in CSF Aβ-oligomer levels were related to cognitive decline. Therefore, CSF Aβ-oligomers may aid in the selection of patients with a more aggressive disease course.Journal of Alzheimer's disease: JAD 12/2014; DOI:10.3233/JAD-142136 · 3.61 Impact Factor
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ABSTRACT: Accumulation of amyloid-β (Aβ) peptides correlates with aging and progression of Alzheimer's disease (AD). Aβ peptides, which cause early synaptic dysfunctions, spine loss, and memory deficits, also disturb intracellular Ca(2+) homeostasis. By cytosolic and endoplasmic reticulum Ca(2+) measurements, we here define the short-term effects of synthetic Aβ42 on neuronal Ca(2+) dynamics. When applied acutely at submicromolar concentration, as either oligomers or monomers, Aβ42 did not cause Ca(2+) release or Ca(2+) influx. Similarly, 1-hour treatment with Aβ42 modified neither the resting cytosolic Ca(2+) level nor the long-lasting Ca(2+) influx caused by KCl-induced depolarization. In contrast, Aβ42 oligomers, but not monomers, significantly altered Ca(2+) release from stores with opposite effects on inositol 1,4,5-trisphosphate (IP3)- and caffeine-induced Ca(2+) mobilization without alteration of the total store Ca(2+) content. Ca(2+) dysregulation by Aβ42 oligomers involves metabotropic glutamate receptor 5 and requires network activity and the intact exo-endocytotic machinery, being prevented by tetrodotoxin and tetanus toxin. These findings support the idea that Ca(2+) store dysfunction is directly involved in Aβ42 neurotoxicity and represents a potential therapeutic target in AD-like dementia. Copyright © 2014 Elsevier Inc. All rights reserved.Neurobiology of Aging 10/2014; DOI:10.1016/j.neurobiolaging.2014.10.020 · 4.85 Impact Factor