The ER stress factor XBP1s prevents amyloid-β neurotoxicity

Alzheimer's disease (AD) is an incurable neurodegenerative disorder clinically characterized by progressive cognitive impairment. A prominent pathologic hallmark in the AD brain is the abnormal accumulation of the amyloid-beta 1-42 peptide (A beta), but the exact pathways mediating A beta neurotoxicity remain enigmatic. Endoplasmic reticulum (ER) stress is induced during AD, and has been indirectly implicated as a mediator of A beta neurotoxicity. We report here that A beta activates the ER stress response factor X-box binding protein 1 (XBP1) in transgenic flies and in mammalian cultured neurons, yielding its active form, the transcription factor XBP1s. XBP1s shows neuroprotective activity in two different AD models, flies expressing A beta and mammalian cultured neurons treated with A beta oligomers. Trying to identify the mechanisms mediating XBP1s neuroprotection, we found that in PC12 cells treated with A beta oligomers, XBP1s prevents the accumulation of free calcium (Ca2+) in the cytosol. This protective activity can be mediated by the downregulation of a specific isoform of the ryanodine Ca2+ channel, RyR3. In support of this observation, a mutation in the only ryanodine receptor (RyR) in flies also suppresses A beta neurotoxicity, indicating the conserved mechanisms between the two AD models. These results underscore the functional relevance of XBP1s in A beta toxicity, and uncover the potential of XBP1 and RyR as targets for AD therapeutics.