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ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology.

Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J - J Neuroinflammation (2009)

Bottom Line: Recent studies have demonstrated that ER stress can also induce an inflammatory response via different UPR transducers.The most potent pathways are IRE1-TRAF2, PERK-eIF2alpha, PERK-GSK-3, ATF6-CREBH, as well as inflammatory caspase-induced signaling pathways.We will describe the mechanisms which could link the ER stress of neurons to the activation of the inflammatory response and the evolution of pathological changes in AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Institute of Clinical Medicine, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. antero.salminen@uku.fi

ABSTRACT
The endoplasmic reticulum (ER) is involved in several crucial cellular functions, e.g. protein folding and quality control, maintenance of Ca2+ balance, and cholesterol synthesis. Many genetic and environmental insults can disturb the function of ER and induce ER stress. ER contains three branches of stress sensors, i.e. IRE1, PERK and ATF6 transducers, which recognize the misfolding of proteins in ER and activate a complex signaling network to generate the unfolded protein response (UPR). Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving misfolding and aggregation of proteins in conjunction with prolonged cellular stress, e.g. in redox regulation and Ca2+ homeostasis. Emerging evidence indicates that the UPR is activated in neurons but not in glial cells in AD brains. Neurons display pPERK, peIF2alpha and pIRE1alpha immunostaining along with abundant diffuse staining of phosphorylated tau protein. Recent studies have demonstrated that ER stress can also induce an inflammatory response via different UPR transducers. The most potent pathways are IRE1-TRAF2, PERK-eIF2alpha, PERK-GSK-3, ATF6-CREBH, as well as inflammatory caspase-induced signaling pathways. We will describe the mechanisms which could link the ER stress of neurons to the activation of the inflammatory response and the evolution of pathological changes in AD.

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A schematic presentation of the three branches of UPR, their signaling pathways, and pathological responses with respect to inflammation and AD pathology.
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Figure 1: A schematic presentation of the three branches of UPR, their signaling pathways, and pathological responses with respect to inflammation and AD pathology.

Mentions: The ER is a membrane-enclosed reticular network connecting the nuclear envelope to the Golgi complex [11]. It has multiple vital functions: (i) protein folding, post-translational modification, and transport to the Golgi complex, (ii) maintenance of cellular calcium homeostasis, (iii) synthesis of lipids and sterols, and (iv) regulation of cellular survival via a complex transducer and signaling network [11-16]. ER is a sensitive sensor of cellular homeostasis and different types of insults, e.g. proteasomal inhibition and impaired redox regulation and calcium balance, can disturb the function of ER and induce ER stress (Figure 1). ER stress involves the accumulation of unfolded and deficiently modified proteins, disturbances in lipid metabolism, and release of ER luminal Ca2+ into the cytoplasm [12,13]. In particular, failure of protein quality control is detrimental to cellular survival and therefore ER can trigger an evolutionarily conserved UPR to counteract the situation [13-16].


ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology.

Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J - J Neuroinflammation (2009)

A schematic presentation of the three branches of UPR, their signaling pathways, and pathological responses with respect to inflammation and AD pathology.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806266&req=5

Figure 1: A schematic presentation of the three branches of UPR, their signaling pathways, and pathological responses with respect to inflammation and AD pathology.
Mentions: The ER is a membrane-enclosed reticular network connecting the nuclear envelope to the Golgi complex [11]. It has multiple vital functions: (i) protein folding, post-translational modification, and transport to the Golgi complex, (ii) maintenance of cellular calcium homeostasis, (iii) synthesis of lipids and sterols, and (iv) regulation of cellular survival via a complex transducer and signaling network [11-16]. ER is a sensitive sensor of cellular homeostasis and different types of insults, e.g. proteasomal inhibition and impaired redox regulation and calcium balance, can disturb the function of ER and induce ER stress (Figure 1). ER stress involves the accumulation of unfolded and deficiently modified proteins, disturbances in lipid metabolism, and release of ER luminal Ca2+ into the cytoplasm [12,13]. In particular, failure of protein quality control is detrimental to cellular survival and therefore ER can trigger an evolutionarily conserved UPR to counteract the situation [13-16].

Bottom Line: Recent studies have demonstrated that ER stress can also induce an inflammatory response via different UPR transducers.The most potent pathways are IRE1-TRAF2, PERK-eIF2alpha, PERK-GSK-3, ATF6-CREBH, as well as inflammatory caspase-induced signaling pathways.We will describe the mechanisms which could link the ER stress of neurons to the activation of the inflammatory response and the evolution of pathological changes in AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Institute of Clinical Medicine, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. antero.salminen@uku.fi

ABSTRACT
The endoplasmic reticulum (ER) is involved in several crucial cellular functions, e.g. protein folding and quality control, maintenance of Ca2+ balance, and cholesterol synthesis. Many genetic and environmental insults can disturb the function of ER and induce ER stress. ER contains three branches of stress sensors, i.e. IRE1, PERK and ATF6 transducers, which recognize the misfolding of proteins in ER and activate a complex signaling network to generate the unfolded protein response (UPR). Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving misfolding and aggregation of proteins in conjunction with prolonged cellular stress, e.g. in redox regulation and Ca2+ homeostasis. Emerging evidence indicates that the UPR is activated in neurons but not in glial cells in AD brains. Neurons display pPERK, peIF2alpha and pIRE1alpha immunostaining along with abundant diffuse staining of phosphorylated tau protein. Recent studies have demonstrated that ER stress can also induce an inflammatory response via different UPR transducers. The most potent pathways are IRE1-TRAF2, PERK-eIF2alpha, PERK-GSK-3, ATF6-CREBH, as well as inflammatory caspase-induced signaling pathways. We will describe the mechanisms which could link the ER stress of neurons to the activation of the inflammatory response and the evolution of pathological changes in AD.

Show MeSH
Related in: MedlinePlus