Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synaptic dysfunction and accumulation of abnormal aggregates formed by amyloid-β peptides or phosphorylated tau proteins. Accumulating evidence suggests that alterations in the buffering capacity of the proteostasis network are a salient feature of AD. The endoplasmic reticulum (ER) is the main compartment involved in protein folding and secretion and is drastically affected in AD neurons. ER stress triggers the activation of the unfolded protein response (UPR), a signal transduction pathway that enforces adaptive programs to recover homeostasis or trigger apoptosis of irreversibly damaged cells. Experimental manipulation of specific UPR signaling modules in preclinical models of AD has revealed a key role of this pathway in regulating protein misfolding and neurodegeneration. Recent studies suggest that the UPR also influences synaptic plasticity and memory through ER stress-independent mechanisms. Consequently, targeting of the UPR in AD is emerging as an interesting therapeutic approach to modify the two pillars of AD, protein misfolding and synaptic failure. Here, we review the functional role of ER stress signaling in AD, discussing the complex involvement of the pathway in controlling neuronal survival, the amyloid cascade, neurodegeneration and synaptic function. Recent intervention efforts to target the UPR with pharmacological and gene therapy strategies are also discussed.

Partial Protection of Paclitaxel-induced Neurotoxicity by Antioxidants

“…Neurotoxicity induced by amyloid-β peptides are caused by mitochondrial dysfunction and oxidative stress (18), alteration of metal ion influx (19), endoplasmic reticulum stress (20) and impaired autophagy (21). Amyloid β-induced neuronal cell death may be partially alleviated by antioxidants (22)(23)(24).…”

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…The cause of impaired proteostasis in AD is still unknown although several hypotheses have been proposed. There is convincing evidence that ER stress is increased in human AD brains and might have a causative role in the pathogenesis of AD [61]. In their seminal study, Hoozemans et al [62] demonstrated that the immunohistochemical staining of phosphorylated pPERK (activated) and UPR chaperone BiP/GRP78 were markedly increased in the neurons of temporal cortex and hippocampus in AD patients.…”

Protection of Differentiating Neuronal Cells from Amyloid β Peptide-induced Injury by Alkaline Extract of Leaves of Sasa senanensis Rehder

“…Aβs have been reported to induce apoptosis in neuronal cells by mitochondrial dysfunction and oxidative 2 , and incubated to achieve complete cell attachment. Cells were treated for 4,8,12,48,72 stress (10), alteration of metal ion influx (11), endoplasmic reticulum stress (12) and impaired autophagy (13). In order to test the generality of cell protective activity of SE, we investigated here whether SE protects the neuronal cell death induced by amyloid β-peptides (Aβ and Aβ [25][26][27][28][29][30][31][32][33][34][35] ).…”