Reduction of calcium release from the endoplasmic reticulum could only provide partial neuroprotection against beta‐amyloid peptide toxicity

Suen, Ka-Chun; Lin, Kim-Fung; Elyaman, Wassim; So, Kwok-Fai; Chang, Raymond Chuen‐Chung; Hugon, Jacques

doi:10.1111/j.1471-4159.2003.02259.x

Cited by 57 publications

(31 citation statements)

References 67 publications

(102 reference statements)

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“…Although it is unclear how extracellular Aβ signals to the ER, it has been shown that extracellular Aβ can induce the UPR [66,67] (data reproduced in our lab, Chafekar and Scheper, unpublished). Aβ induces Ca 2+ release from the ER [68] and inhibition of Ca 2+ release, which concomitantly attenuates the upregulation of BiP, partly relieves Aβ toxicity [66].…”

Section: A Role For Presenilin In Upr Signalingsupporting

confidence: 54%

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Protein Quality Control in Alzheimers Disease: A Fatal Saviour

Scheper

Hol²

2005

CDTCNSND

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Aggregation of Abeta plays a key role in the pathogenesis of Alzheimer's disease. Although the highly structured Abeta aggregates (fibrils) have long been thought to be the toxic form of Abeta, recent evidence suggests that smaller, soluble intermediates in Abeta aggregation are the real culprit. Because these oligomeric aggregates are already formed in the secretory pathway, this raises another issue: Is intra- or extracellular Abeta involved in the pathogenic cascade? Because aggregated proteins are very toxic, cells have developed quality control responses to deal with such proteins. A prime site for quality culum. Here, aberrant proteins are recognized and can be targeted for degradation to the cytosolic quality control system. In addition, there is accumulating evidence for quality control in other subcellular compartments in the cell. All quality control mechanisms are initially protective, but will become destructive after prolonged accumulation of aggregated proteins. This is enhanced by decreased efficiency of these systems during aging and therefore, these responses may play an important role in the pathogenesis of Alzheimer's disease. In this review, we will discuss the role of protein quality control in the neurotoxicity of Abeta.

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Section: A Role For Presenilin In Upr Signalingsupporting

confidence: 54%

“…Aβ induces Ca 2+ release from the ER [68] and inhibition of Ca 2+ release, which concomitantly attenuates the upregulation of BiP, partly relieves Aβ toxicity [66]. In contrast, upregulation of BiP was suggested to be protective in Aβ toxicity [67].…”

Section: A Role For Presenilin In Upr Signalingmentioning

confidence: 97%

Protein Quality Control in Alzheimers Disease: A Fatal Saviour

Scheper

Hol²

2005

CDTCNSND

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“…Diverse studies have demonstrated that A -42 signals to the ER and induces the UPR [164,165]. It has been shown that caspase-12 deficient neurons have reduced sensitivity to A peptide [158].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

The Stress Rheostat: An Interplay Between the Unfolded Protein Response (UPR) and Autophagy in Neurodegeneration

Matus

Lisbona²,

Torres³

et al. 2008

CMM

122

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The unfolded protein response (UPR) is a conserved adaptive reaction that increases cell survival under conditions of endoplasmic reticulum (ER) stress. The UPR controls diverse processes such as protein folding, secretion, ER biogenesis, protein quality control and macroautophagy. Occurrence of chronic ER stress has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation, including Amyotrophic lateral sclerosis, Prion-related disorders, and conditions such as Parkinson's, Huntington's, and Alzheimer's disease. Strong correlations are observed between disease progression, accumulation of protein aggregates, and induction of the UPR in animal and in vitro models of neurodegeneration. In addition, the first reports are available describing the engagement of ER stress responses in brain post-mortem samples from human patients. Despite such findings, the role of the UPR in the central nervous system has not been addressed directly and its contribution to neurodegeneration remains speculative. Recently, however, pharmacological manipulation of ER stress and autophagy - a stress pathway modulated by the UPR - using chemical chaperones and autophagy activators has shown therapeutic benefits by attenuating protein misfolding in models of neurodegenerative disease. The most recent evidence addressing the role of the UPR and ER stress in neurodegenerative disorders is reviewed here, along with therapeutic strategies to alleviate ER stress in a disease context.

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“…Disrupted ER Ca 2+ homeostasis has been suggested to have a key role in the pathogenesis of AD (reviewed in [197]). In particular, the ability of Aβ to evoke Ca 2+ leakage from IP 3 and ryanodine receptors in ER has been shown to be involved in the activation of apoptotic death in cells stressed with Aβ peptides [198][199][200].…”

Section: Mitochondria and Endoplasmic Reticulum Dysfunctionmentioning

confidence: 99%

Alzheimers Disease-Associated Neurotoxic Mechanisms and Neuroprotective Strategies

Pereira¹,

Agostinho²,

Moreira³

et al. 2005

CDTCNSND

115

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The characteristic hallmarks of Alzheimer's disease (AD), the most common form of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid (Abeta) peptide, neurofibrillary tangles and selective synaptic and neuronal loss in brain regions involved in learning and memory. Genetic studies, together with the demonstration of Abeta neurotoxicity, led to the development of the amyloid cascade hypothesis to explain the AD-associated neurodegenerative process. However, a modified version of this hypothesis has emerged, the Abeta cascade hypothesis, which takes into account the fact that soluble oligomeric forms and protofibrils of Abeta and its intraneuronal accumulation also play a key role in the pathogenesis of the disease. Recent evidence posit that synaptic dysfunction triggered by non fibrillar Abeta species is an early event involved in memory decline in AD. The current understanding of the molecular mechanisms responsible for impaired synaptic function and cognitive deficits is outlined in this review, focusing on oxidative stress and disturbed metal ion homeostasis, Ca(2+) dysregulation, mitochondria and endoplasmic reticulum dysfunction, cholesterol dyshomeostasis and impaired neurotransmission. The activation of apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent role of neuroinflammation in this neurodegenerative disorder, are also reviewed herein. Furthermore, we will focus on the more relevant therapeutical strategies currently used, namely those involving antioxidants, drugs for neurotransmission improvement, hormonal replacement, gamma- and beta- secretase inhibitors, Abeta clearance agents (Abeta immunization, disruption of Abeta fibrils, modulation of the cholesterol-mediated Abeta transport), non-steroidal anti-inflammatory drugs (NSAIDs), microtubules stabilizing drugs and kinase inhibitors.

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Reduction of calcium release from the endoplasmic reticulum could only provide partial neuroprotection against beta‐amyloid peptide toxicity

Cited by 57 publications

References 67 publications

Protein Quality Control in Alzheimers Disease: A Fatal Saviour

Protein Quality Control in Alzheimers Disease: A Fatal Saviour

The Stress Rheostat: An Interplay Between the Unfolded Protein Response (UPR) and Autophagy in Neurodegeneration

Alzheimers Disease-Associated Neurotoxic Mechanisms and Neuroprotective Strategies

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