Inhibitors of Aβ42-induced endoplasmic reticular unfolded protein response (UPR^ER), in yeast, also rescue yeast cells from Aβ42-mediated apoptosis

Aggregated Aβ peptides which cause amyloid deposits, a characteristic of Alzheimer's disease (AD), activate a stress response in the endoplasmic reticulum (ER), known as the unfolded protein response, UPR^ER. Nascent UPR^ER induction helps in reducing ER stress by eliminating accumulated misfolded/aggregated secretory proteins. However, prolonged UPR^ER induction may trigger apoptosis. Here we show that, when expressed in yeast with an NH₂-terminal secretory signal sequence (ss), the 42-amino acid human Aβ42 (h_Aβ42), but not the mouse/ratAβ42 (m_Aβ42) which reportedly does not misfold/aggregate, induces UPR^ER as monitored via an eGFP reporter. We also show that expression of ss-h_Aβ42, not ss-m_Aβ42, blocks yeast cell growth, with cells expressing ss-h_Aβ42 manifesting distinctive features of apoptosis such as loss of mitochondrial membrane potential, increase in ROS levels and DNA fragmentation. Screening for suppressors of ss-h_Aβ42-activated UPR^ER-eGFP induction, in a computationally-designed 29-compound methoxy-stilbene library, revealed three compounds that reduce >95% of UPR^ER-eGFP induction at 5 μM concentration, with EC₅₀ values of 40–50 nM. Surprisingly, the compounds also rescue yeast cells from ss-h_Aβ42-mediated apoptosis, with EC₅₀-s of 50–60 nM. These results provide direct evidence, probably for the first time, that there is a direct correlation between deactivation of UPR^ER and attenuation of apoptosis.