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

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, peIF2α and pIRE1α 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-eIF2α, 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.

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…It remains to be clarified whether phosphorylation induced tau LLPS occurs as cause or result of tau mislocalization into the somato‐dendritic compartment of neurons. (iii) The intraneuronal accumulation of tau droplets and aggregated tau in the cell body (e.g., in NFTs) causes not only long‐term toxicity through ER stress and UPR (Salminen et al , 2009), but it also depletes tau from the soluble pool that is essential to maintain microtubule stability. Tau droplets could also have other direct pathological consequences, for example, through aberrant interaction with cellular organelles or “absorption” of RNA molecules, which would impact protein expression and homeostasis of the neuron.…”

Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway

“…ER stress is implicated in the development or pathology of AD [15][16][17] . [21] , insulin resistance of adipose tissue [38] , apoptosis of osteoblastic cells [39] , type 2 diabetes mellitus [40] , and hepatic steatosis [41] .…”

“…Emerging evidence indicates that endoplasmic reticulum (ER) stress plays a pivotal role in the development or pathology of AD, which is characterized by an abnormal formation of inclusion bodies and aggregation of misfolded proteins [15][16][17] . The ER is a sophisticated luminal network for the synthesis, www.nature.com/aps Wei HJ et al Acta Pharmacologica Sinica npg maturation, folding, and transportation of proteins, which are required for cell survival and normal cellular functions [18,19] .…”

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

“…17 This becomes a self-perpetuating pathological process, with each pathologic component exacerbating the others. [22][23][24][25][26] We have shown that aspirin, ibuprofen, and resveratrol dampen the PSACH chondrocyte pathology, reducing inflammation and/or oxidative stress. 16 This important and novel therapeutic approach interrupts the pathological loop.…”