Mechanisms of neuronal death in disease: defining the models and the players

Ribé, Elena M.; Serrano-Saiz, Esther; Akpan, Nsikan; Troy, Carol M.

doi:10.1042/bj20081118

Cited by 91 publications

(67 citation statements)

References 202 publications

(217 reference statements)

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“…Cytochrome c is released from mitochondrial inter-membrane space following cerebral ischemia [30] along with other apoptogenic proteins such as caspase-9 which cleaves and activates downstream caspases such as caspase-3 and caspase-7 [31]. These caspases have an executioner role in death mechanism.…”

Section: Discussionmentioning

confidence: 99%

Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis

et al. 2011

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Brain ischemia has major consequences leading to the apoptosis of astrocytes and neurons. Glucose-regulated protein 78 (GRP78) known for its role in endoplasmic reticulum stress alleviation was discovered on several cell surfaces acting as a receptor for signaling pathways. We have previously described peptides that bind cell surface GRP78 on endothelial cells to induce angiogenesis. We have also reported that ADoPep1 binds cardiomyocytes to prevent apoptosis of ischemic heart cells. In this study we describe the effect of hypoxia on astrocytes and neurons cell surface GRP78. Under hypoxic conditions, there was an increase of more than fivefold in GRP78 on cell surface of neurons while astrocytes were not affected. The addition of the GRP78 binding peptide, ADoPep1, to neurons decreased the percentage of GRP78 positive cells and did not change the percent of astrocytes. However, a significant increase in early and late apoptosis of both astrocytes and neurons under hypoxia was attenuated in the presence of ADoPep1. Intravitreal administration of ADoPep1 to mice in a model of optic nerve crush significantly reduced retinal cell loss after 21 days compared to the crush-damaged eyes without treatment or by control saline vehicle injection. Histological staining demonstrated reduced GRP78 after ADoPep1 treatment. The mechanism of peptide neuroprotection was demonstrated by the inhibition of hypoxia induced caspase 3/7 activity, cytochrome c release and p38 phosphorylation. This study is the first report on hypoxic neuronal and astrocyte cell surface GRP78 and suggests a potential therapeutic target for neuroprotection.

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Section: Discussionmentioning

confidence: 99%

Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis

et al. 2011

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“…23 Cerebellar homogenates from Tg(⌬CR)/Prn-p ϩ/0 mice at 15 or 20 days of age, as well as from rescue and nontransgenic littermates did not contain detectable caspase-8 activity ( Figure 1D, white bar and striped bar). As a positive control, caspase-8 activity was detected in normal cerebellar homogenates supplemented with recombinant enzyme ( Figure 1D, black bar).…”

Section: Neuronal Death In Tg(⌬cr) Mice Is Not Accompanied By Activatmentioning

confidence: 99%

A Highly Toxic Cellular Prion Protein Induces a Novel, Nonapoptotic Form of Neuronal Death

Christensen

Dikranian

et al. 2010

The American Journal of Pathology

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Several different deletions within the N-terminal tail of the prion protein (PrP) induce massive neuronal death when expressed in transgenic mice. This toxicity is dose-dependently suppressed by coexpression of full-length PrP, suggesting that it results from subversion of a normal physiological activity of cellular PrP. We performed a combined biochemical and morphological analysis of Tg(⌬CR) mice, which express PrP carrying a 21-aa deletion (residues 105-125) within a highly conserved region of the protein. Death of cerebellar granule neurons in Tg(⌬CR) mice is not accompanied by activation of either caspase-3 or caspase-8 or by increased levels of the autophagy marker, LC3-II. In electron micrographs, degenerating granule neurons displayed a unique morphology characterized by heterogeneous condensation of the nuclear matrix without formation of discrete chromatin masses typical of neuronal apoptosis. Our data demonstrate that perturbations in PrP functional activity induce a novel , nonapoptotic , nonautophagic form of neuronal death whose morphological features are reminiscent of those associated with excitotoxic stress.

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“…There is substantial evidence to suggest that at least a subset of neurons in the AD brain die by apoptosis (2). The principal neuropathological hallmark of the disease, ␤-amyloid peptide (A␤), has been shown to induce apoptosis in neuronal cells in vivo and in vitro (3,4) through a variety of enzymatic pathways that include activation of caspase-3 (5), calpain (6,7), and lysosomal cathepsins (8,9).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Noonan

Tanveer

Klompas

et al. 2010

Journal of Biological Chemistry

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Neuronal cell loss underlies the pathological decline in cognition and memory associated with Alzheimer disease (AD).Recently, targeting the endocannabinoid system in AD has emerged as a promising new approach to treatment. Studies have identified neuroprotective roles for endocannabinoids against key pathological events in the AD brain, including cell death by apoptosis. Elucidation of the apoptotic pathway evoked by ␤-amyloid (A␤) is thus important for the development of therapeutic strategies that can thwart A␤ toxicity and preserve cell viability. We have previously reported that lysosomal membrane permeabilization plays a distinct role in the apoptotic pathway initiated by A␤. In the present study, we provide evidence that the endocannabinoid system can stabilize lysosomes against A␤-induced permeabilization and in turn sustain cell survival. We report that endocannabinoids stabilize lysosomes by preventing the A␤-induced up-regulation of the tumor suppressor protein, p53, and its interaction with the lysosomal membrane. We also provide evidence that intracellular cannabinoid type 1 receptors play a role in stabilizing lysosomes against A␤ toxicity and thus highlight the functionality of these receptors. Given the deleterious effect of lysosomal membrane permeabilization on cell viability, stabilization of lysosomes with endocannabinoids may represent a novel mechanism by which these lipid modulators confer neuroprotection. Alzheimer disease (AD)2 is a debilitating illness of the brain defined by the progressive deterioration of cognition and memory as a result of selective neuronal loss in the hippocampus and surrounding areas of the cerebral cortex (1). There is substantial evidence to suggest that at least a subset of neurons in the AD brain die by apoptosis (2). The principal neuropathological hallmark of the disease, ␤-amyloid peptide (A␤), has been shown to induce apoptosis in neuronal cells in vivo and in vitro (3, 4) through a variety of enzymatic pathways that include activation of caspase-3 (5), calpain (6, 7), and lysosomal cathepsins (8, 9).Recently, the lysosomal system has been implicated in AD pathogenesis (9, 10). Neurons of AD patients demonstrate alterations in the lysosomal system, including the cellular pathways that converge on it, namely endocytosis and autophagy (10, 11). Such alterations include an increase in the size and number of endosomes (10, 12), autophagosomes (13) and lysosomes (10) and an increase in the gene expression and synthesis of all classes of lysosomal hydrolases, including cathepsins (14). In addition to their role in the digestion of cellular waste, it has become clear that partial and selective lysosomal membrane permeabilization (LMP), followed by the release of lysosomal enzymes into the cytosol, can induce apoptotic cell death (15). Cathepsins D and L are among the lysosomal proteases that have been implicated in apoptosis by virtue of their ability to activate apoptotic effectors, such as mitochondrial uncoupling and caspases (16).Among the agents that are ca...

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Mechanisms of neuronal death in disease: defining the models and the players

Cited by 91 publications

References 202 publications

Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis

Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis

A Highly Toxic Cellular Prion Protein Induces a Novel, Nonapoptotic Form of Neuronal Death

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

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