Protein aggregation and ER stress. Ogen-Shtern Navit,Ben David Tamuz,Lederkremer Gerardo Z Brain research Protein aggregation is a common feature of the protein misfolding or conformational diseases, among them most of the neurodegenerative diseases. These disorders are a major scourge, with scarce if any effective therapies at present. Recent research has identified ER stress as a major mechanism implicated in cytotoxicity in these diseases. Whether amyloid-β or tau in Alzheimer's, α-synuclein in Parkinson's, huntingtin in Huntington's disease or other aggregation-prone proteins in many other neurodegenerative diseases, there is a shared pathway of oligomerization and aggregation into amyloid fibrils. There is increasing evidence in recent years that the toxic species, and those that evoke ER stress, are the intermediate oligomeric forms and not the final amyloid aggregates. This review focuses on recent findings on the mechanisms and importance of the development of ER stress upon protein aggregation, especially in neurodegenerative diseases, and possible therapeutic approaches that are being examined. This article is part of a Special Issue entitled SI:ER stress. 10.1016/j.brainres.2016.03.044

Molecular mechanism aspect of ER stress in Alzheimer's disease: current approaches and future strategies. Ansari Niloufar,Khodagholi Fariba Current drug targets Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by progressive loss of memory and cognitive impairment. Aggregation of amyloid-β (Aβ) peptides is the crucial factor in the onset of AD. The toxic Aβ peptides Aβ40 and Aβ42 are produced from the Aβ precursor protein (APP), a transmembrane protein which is folded and modified in endoplasmic reticulum (ER). ER is the main organelle for the synthesis and processing of nearly all proteins as well as the main cellular source of Ca2+. Under stress conditions, three main ER pathways including inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor 6 become activated causing the accumulation of unfolded or misfolded proteins within ER lumen. These pathways manage the stress by regulating the expression of chaperones and enzymes involved in protein folding. Several studies have reported the dysfunction of these stress-sensing pathways in pathological conditions, including neurodegenerative diseases. Recent studies have proposed that neuronal death in AD arises from dysfunction of the ER. Here, we will review recent research findings on the interaction between ER and mitochondria, and its effect on apoptotic pathways. We further provide insights into studies which suggest the role of ER in animal and/or cellular models of AD. Therapeutic strategies that modulate ER could represent a promising approach for prevention or treatment of AD.

Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer's disease. Takuma Kazuhiro,Yan Shirley Shidu,Stern David M,Yamada Kiyofumi Journal of pharmacological sciences Alzheimer's disease (AD) is the most common neurodegenerative disorder of late life characterized by insidious, chronic, and progressive memory impairment in association with the accumulation of senile plaques, neurofibrillary tangles, and massive loss of neurons. Apoptosis is believed to be an important contributor to progression and pathology of neurodegeneration in AD. There is considerable evidence that amyloid beta-peptide, a major component of senile plaques, has the capacity to activate intracellular apoptosis pathways leading to neuronal cell death. AD-related mutations in genes coding presenilins are also shown to cause neuronal apoptosis, by directly and indirectly regulating apoptotic signaling cascades. Recent evidence suggests that two intrinsic pathways, mitochondrial dysfunction and endoplasmic reticulum stress, are central in the execution of apoptosis in AD. This review summarizes recent progress of research in this field focused on the molecular mechanisms involved in neuronal apoptosis mediated by organelle dysfunction.

Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Fonseca Ana Catarina R G,Ferreiro Elisabete,Oliveira Catarina R,Cardoso Sandra M,Pereira Cláudia F Biochimica et biophysica acta Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration. 10.1016/j.bbadis.2013.08.007