The IRE1-XBP1 branch of the UPR delays amyloid beta accumulation and neurotoxicity in Drosophila CNS; implications for AD

LAUTARO I BELFIORI-CARRASCO; EDUARDO M CASTAÑO; MARIA S MARCORA; LAURA MORELLI; NADIA I BOCAI

Coimbra

Conferencia; Special Conference of the International Society of Neurochemistry (ISN). Synaptic Function and Dysfunction in Brain Diseases; 2016

ISN

Alzheimers disease (AD) is associated to accumulationof amyloid beta (Aβ) peptide in specific brain areas, leading to neuronaldysfunction. Growing evidence suggest that Aβ accumulation induces ER stress inearly stages of AD. Disturbed ER homeostasis engages an adaptive reaction knownas the unfolded protein response (UPR) that protects the cell against toxicmisfolded proteins. IRE1 activation, the most conserved UPR branch, includesthe unconventional splicing of X-Box-binding protein 1 (XBP1s), a transcription factor that up-regulates genes related to protein folding and ER-mediated degradation. Specific markers for UPR activation have been detected in AD brain tissues including deregulation of XBP1 signaling. Here, we use Drosophila melanogaster as a model to study early events in Aβ toxicity. Neuronal, but not glial Aβ expression caused progressive impairment in climbing ability, first evidenced in 18 days old flies (p