ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology.
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.
Salminen
Antero
A
Department of Neurology, Institute of Clinical Medicine, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. antero.salminen@uku.fi
Kauppinen
Anu
A
Suuronen
Tiina
T
Kaarniranta
Kai
K
Ojala
Johanna
J
D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D004660:Encephalitis / Q000503:physiopathology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006801:Humans; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology; D015398:Signal Transduction; D013312:Stress, Physiological / Q000502:physiology*