Nowadays more than 24 million people suffer from Alzheimer's disease (AD) that is the most common progressive cause of dementia. Molecular mechanisms of neurodegeneration in Alzheimer's disease is closely link with accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER). Deposition of senile plaques is one of the main feature of Alzheimer's disease as well as is strictly correlated with impairment of cognitive abilities. The accumulation of misfolded proteins in the lumen of the ER triggers activation of the ER stress, and subsequently unfolded protein response (UPR) signaling branches, which consists of a cascade of events on the molecular level of nerve cell. That results in attenuation of global protein translation mediated by the activated Protein kinase RNA-like endoplasmic reticulum kinase (PERK) through phosphorylation of eukaryotic initiation factor 2α (eIF2α). On the contrary, prolonged ER stress contributes to preferential translation of proteins such as Activating Transcription Factor 4 (ATF4) and CCAAT-enhancer binding protein homologous protein (CHOP) engaged in apoptotic cell death. Moreover, ensues preferential translation of enzyme beta-secretase 1 (BACE1), which is an enzyme involved in deposition of senile plagues in brain tissue, that are the main cause of cognitive impairment. Recent molecular and genetic investigations present a new point of view on the therapeutic strategy for AD. Deactivation of PERK kinase via smallmolecule inhibitors has been identified as a potential therapeutic target. It is highly possible that the inhibition of PERK activity may contribute to preventing the excessive accumulation of senile plaques among the neurons and, as a result, neuronal loss and significant decline in cognitive abilities in AD.
Keywords: Alzheimer’s disease; PERK kinase; apoptosis; endoplasmic reticulum stress; small-molecule inhibitors.
© 2016 MEDPRESS.