Amyloid B42 clearance and neuroprotection mediated by XBP1 signaling decline with aging in the Drosophila brain

MARCORA M.S; BELFIORI-CARRASCO LF; BOCAI NI; MORELLI L; CASTAÑO E.M

neurobiology of aging

ElSevier

Año: 2017

The unfolded protein response (UPR) may be pathogenically related to Alzheimer?s disease. Yet, the effects of chronic amyloid-b42 (Ab42) accumulation and UPR activation upon neurotoxicity remain unclear. Here, we show that neuronal Ab42 expression in Drosophila activated the inositol-requiring protein-1/X-box binding protein 1 (XBP1) UPR branch before the onset of behavioral impairment and persisted with aging. Early upregulation of hsc3/BiP, a target of XBP1 and activating transcription factor 6 pathways, was also sustained in old animals. Downregulation of XBP1 enhanced neurotoxicity and the accumulation of Ab42 and polyubiquitinated proteins. Consistently, overexpression of spliced XBP1 reduced Ab42 and improved geotaxis in old flies. The activation of protein kinase RNA-like endoplasmic reticulum (ER) kinase contributed to the age-dependent geotaxis deficit. Spliced XBP1 gene targets ER degradation-enhancing mannosidase-like protein 1, ER degradation-enhancing mannosidase-like protein 2, and HRD1 were elevated in 5-day-old Ab42-expressing flies as compared to controls but not in 18-dayold flies. Our results indicate that inositol-requiring protein-1/XBP1 activation is neuroprotective and enhances Ab42 clearance. They also suggest that such response becomes inefficient with aging