Expression of invariant chain and pro-cathepsin L in Alzheimer's brain

Yoshiyama, Yasumasa; Arai, Kimihito; Oki, Takeshi; Hattori, Takamichi

doi:10.1016/s0304-3940(00)01326-4

Cited by 29 publications

(22 citation statements)

References 15 publications

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“…2003). Cathepsin B and L mRNAs are up‐regulated in neuropathological conditions, such as Alzheimer's disease (Yoshiyama et al . 2000; Gan et al .…”

Section: Discussionmentioning

confidence: 99%

“…particular, cathepsin B and cathepsin L are expressed in the adult mammalian retina (Bernstein et al 1989;Frohlich and Klessen 2001;Koike et al 2003;Wasselius et al 2003). Cathepsin B and L mRNAs are up-regulated in neuropathological conditions, such as Alzheimer's disease (Yoshiyama et al 2000;Gan et al 2004). Although the essential role of these two cathepsins for maturation and integrity of the postnatal central nervous system has been demonstrated by the phenotype of homozygous double mutant mice for cathepsin B and cathepsin L, which show brain atrophy (Felbor et al 2002), their putative role as executors of developmental cell death has not been explored.…”

Section: Discussionmentioning

confidence: 99%

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Proinsulin/insulin is synthesized locally and prevents caspase‐ and cathepsin‐mediated cell death in the embryonic mouse retina

Valenciano

Corrochano

Pablo

et al. 2006

Journal of Neurochemistry

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Programmed cell death is an essential, highly regulated process in neural development. Although the role of insulin-like growth factor I in supporting the survival of neural cells has been well characterized, studies on proinsulin/insulin are scarce. Here, we characterize proinsulin/insulin effects on cell death in embryonic day 15.5 mouse retina. Both proinsulin mRNA and proinsulin/insulin immunoreactivity were found in the developing retina. Organotypic embryonic day 15.5 retinas cultured under growth factor deprivation showed an increase in cell death that was reversed by proinsulin, insulin and insulin-like growth factor I, with similar median effective concentration values via phosphatidylinositol-3-kinase activation. Although insulin and insulin-like growth factor I provoked a sustained Akt phosphorylation, proinsulin-induced phosphorylation of Akt was not found. Analysis of the growth factor deprivation-induced cell death mechanisms, using caspase and cathepsin inhibitors, demonstrated that both protease families were required for the effective execution of cell death. The insulin survival effect, which decreased the extent and distribution of cell death to levels similar to those found in vivo, was not enhanced by simultaneous treatment with caspase and cathepsin inhibitors, suggesting that insulin interferes with these protease pathways in the embryonic mouse retina. The mechanisms characterized in this study provide new details on early neural cell death and its genuine regulation by insulin/ proinsulin. Keywords: Akt, apoptosis, insulin-like growth factor I, neurogenesis, phosphatidylinositol-3-kinase, programmed cell death. In vitro approaches using transfected cell lines have elucidated several regulatory mechanisms of programmed cell death, although analysis in primary systems has been limited (Strasser et al. 2000;Joza et al. 2002). The vertebrate neuroretina, a part of the central nervous system, provides a model system to study the regulation of cell death, recognized as apoptosis, in a physiological context. Of the defined developmental periods of apoptosis in the vertebrate retina, the best characterized is a late phase in the second half of retinal development, which coincides with neuronal connectivity and synaptogenesis (Glücksmann 1940;Young 1984;Provis and van Driel 1985;Maslim et al. 1997;Marin-Teva et al. 1999). An earlier, less well-characterized phase of programmed cell death takes place in the first half of retinal development (Penfold and Provis 1986;Hensey and Gautier 1998;Diaz et al. 1999Diaz et al. , 2000Laemle et al. 1999;Biehlmaier et al. 2001). Address correspondence and reprint requests to Enrique J. de la Rosa, Centro de Investigaciones Bioló gicas, CSIC, C/Ramiro de Maeztu 9, 28040 Madrid, Spain. E-mail: ejdelarosa@cib.csic.esAbbreviations used: BrdU, bromodeoxyuridine; E, day of embryonic development; EC 50 , median effective concentration; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IGF, insulin-like growth factor; IR, insulin receptor; PI3K, phosphatidylinos...

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“…2003). Cathepsin B and L mRNAs are up‐regulated in neuropathological conditions, such as Alzheimer's disease (Yoshiyama et al . 2000; Gan et al .…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proinsulin/insulin is synthesized locally and prevents caspase‐ and cathepsin‐mediated cell death in the embryonic mouse retina

Valenciano

Corrochano

Pablo

et al. 2006

Journal of Neurochemistry

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“…2001), Ia‐associated invariant chain, also expressed by activated microglia in AD brains (Matza et al . 2003; Yoshiyama et al . 2000), and procollagen‐proline, 2‐oxoglutarate 4‐dioxygenase (proline 4‐hydroxylase), alpha II polypeptide (Kivirikko and Myllyharju 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Down-regulation of Fkbp11 and Dnajc3 could increase the accumulation of unfolded proteins, thus stimulating UPR and ER stress in cholinergic cells. Other genes differentially expressed that are also involved in protein folding were Ero1-like b (Pagani et al 2000;Mezghrani et al 2001), Ia-associated invariant chain, also expressed by activated microglia in AD brains (Matza et al 2003;Yoshiyama et al 2000), and procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), alpha II polypeptide (Kivirikko and Myllyharju 1998). Disruptions in protein glycosylation by down-regulation of defender against cell death (Dad1), an integral ER membrane protein required for N-glycosylation of proteins (Kelleher and Gilmore 1997;Makishima et al 1997), could also activate UPR in these cells.…”

Section: Discussionmentioning

confidence: 99%

Toxicity mediated by soluble oligomers of β‐amyloid(1–42) on cholinergic SN56.B5.G4 cells

Heinitz¹,

Beck

Schliebs³

et al. 2006

Journal of Neurochemistry

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Alzheimer's disease (AD) is characterized by cholinergic dysfunction and progressive basal forebrain cell loss which has been assumed to be as a result of the extensive accumulation of b-amyloid (Ab). In addition to Ab fibrillar assemblies, there are pre-fibrillar forms that have been shown to be neurotoxic, although their role in cholinergic degeneration is still not known. Using the cholinergic cell line SN56.B5.G4, we investigated the effect of different Ab(1-42) aggregates on cell viability. In our model, only soluble oligomeric but not fibrillar Ab(1-42) forms induced toxicity in cholinergic cells. To determine whether the neurotoxicity of oligomeric Ab(1-42) was caused by its oxidative potential, we performed microarray analysis of SN56.B5.G4 cells treated either with oligomeric Ab(1-42) or H 2 O 2 . We showed that genes affected by Ab(1-42) differed from those affected by non-specific oxidative stress. Many of the genes affected by Ab(1-42) were present in the endoplasmic reticulum (ER), Golgi apparatus and/or otherwise involved in protein modification and degradation (chaperones, ATF6), indicating a possible role for ER-mediated stress in Ab-mediated toxicity. Moreover, a number of genes, which are known to be involved in AD (clusterin, Slc18a3), were identified. This study provides important leads for the understanding of oligomeric Ab(1-42) toxicity in cholinergic cells, which may account in part for cholinergic degeneration in AD.

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“…37 Furthermore, in brain tissue from Alzheimersdiseased patients, pro-cathepsin L generation accompanies full activation of microglial cells, but not resting or moderately activated cells. 38 Hence, in the CNS, cathepsin L production during acute injury appears to be reactive. In the context of the neurovascular unit, these experiments suggest that cathepsin L may have roles in neuron-microvessel biology.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin L Acutely Alters Microvessel Integrity within the Neurovascular Unit during Focal Cerebral Ischemia

Kanazawa

Hung

et al. 2015

J Cereb Blood Flow Metab

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During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage.

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Expression of invariant chain and pro-cathepsin L in Alzheimer's brain

Cited by 29 publications

References 15 publications

Proinsulin/insulin is synthesized locally and prevents caspase‐ and cathepsin‐mediated cell death in the embryonic mouse retina

Proinsulin/insulin is synthesized locally and prevents caspase‐ and cathepsin‐mediated cell death in the embryonic mouse retina

Toxicity mediated by soluble oligomers of β‐amyloid(1–42) on cholinergic SN56.B5.G4 cells

Cathepsin L Acutely Alters Microvessel Integrity within the Neurovascular Unit during Focal Cerebral Ischemia

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