Fig. 3: Constitutive ER stress and maladaptive UPR signaling.
From: ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments
Constitutive ER stress triggers maladaptive UPR signaling characterized by excessive activation of the UPR branches. Hyperactivated PERK signaling leads to the activation of NFKB1, igniting neuroinflammation. Prolonged phosphorylation of eIF2alpha causes a block in the synthesis of crucial synaptic and other proteins necessary for neuronal functions. In addition, hyperactivated ATF4 results in an excessive upregulation of DDIT3 and DDIT4 genes with an enhanced expression of autophagy genes, which is detrimental to neurons. Likewise, NFE2L2-induced hyper-transactivation of autophagy genes will lead to excessive autophagy. Overactive IRE1 will lead to massive degradation of mRNAs, being referred to as the RIDD (regulated Ire1-dependent decay), and subsequent induction of apoptosis and neuroinflammation. MAPK8 contributes to excessive autophagy via an enhanced upregulation of autophagy genes and ATF6- and ATF4-transactivated DDIT3 upregulates pro-apoptotic genes, leading to neuronal cell death. DDIT3-induced upregulation of the TXNIP gene, encoding a transcription factor, upregulates neuroinflammatory genes, and promotes the formation of the NLRP3 inflammasome, leading to neuroinflammation. Overall, a maladaptive UPR is characterized by excessive autophagy, apoptosis, and severe neuroinflammation, worsening the pathology observed in AD.
