Aggregation/collapse of endoplasmic reticulum prior activaton of programmed cell death

Abstract

Numerous neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s diseases, Hintington’s disease and prion disease share the common sign of misfolded protein accumulation. Accumulation of misfolded proteins induce endoplasmic reticulum (ER) stress and lead to the activation of unfolded protein responses (UPR). Activation of UPR is a protective mechanism to prevent the accumulation of unfolded/misfolded proteins in the ER lumen. Alzheimer’s disease (AD) is a chronic neurodegenerative disease featured with the accumulation of aggregated beta amyloid (Aβ). It is still unclear whether the occurrence of ER stress signals in AD is neuroprotective or the cause of neuronal death. Moreover, the relationship of ER stress responses and accumulation of Aβ peptide remains unclear. Extracellular application of Aβ peptide has been widely used in in vitro model for AD research. It is shown that extracellular Aβ triggers release of ER calcium. However, our results showed that accumulation of fibrillar Aβ peptide does not induce UPR. The exact mechanism for these phenomena is not clear. Here we report that sublethal concentration of oligomeric Aβ1-40 could not significantly elicit UPR, which may be due to the early aggregation/collapse of the ER. This event occurs prior to the activation of caspase-3. The inhibition of ubiquitin-proteosome system and the stabilization of microtubule partially attenuate the aggregation/collapse of the ER. Prolonged exposure to Aβ leads to aggregation/collapse of the ER and results in the formation of autophagolysosomes. The loss of UPR by oligomeric Aβ-induces aggregation/collapse of the ER may be a new mode of degenerative process and represents the early pathological changes in AD.