Keywords: g. unfolded protein response; a. neural degeneration
Accumulation of abnormal aggregates formed by amyloid-β (Aβ) peptides and synaptic dysfunction are characteristics of Alzheimer’s disease (AD). The accumulation of Aβ fragments during AD results in endoplasmic reticulum stress activating unfolded protein response (UPR) to restore proteostasis and can lead to synapse dysfunction and neurodegeneration. UPR is initiated by activation of stress sensors including the protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor (ATF). UPR-inhibiting drugs are currently under investigation as a possible approach to modulate the metabolism of the Aβ precursor, amyloid precursor protein, and neuroplasticity. To assess the contribution of the UPR to Aβ load, we pharmacologically inhibited the UPR in a Drosophila AD model. Aβ levels were measured in AD model flies raised on STF-083010 and MKC-3946 ( IRE1 inhibitors), GSK2656157 (a PERK kinase inhibitor), and the chemical chaperone Tauroursodeoxycholic acid. We find that AD model animals raised on 10 µM STF-083010 and 50 µM STF-083010 show decreased Aβ loads compared to control AD model animals. In another approach, we examined the effects of Rab11 on Aβ load. Rab11 is a GTPase that facilitates vesicle trafficking from the recycling endosome to the plasma membrane. Vesicle trafficking defects are characteristic of late-onset Alzheimer’s disease. Our collective results will provide insight on the contribution of both Rab11 and the UPR to Aβ load and synaptic dysfunction.