Aβ toxicity rescued by protein retention in the ER

Abstract

Accumulation of A{beta} in the brain is one of the hallmarks of Alzheimers disease (AD). In the adult Drosophila brain, human A{beta} over-expression is toxic and leads to deterioration of climbing ability and shortened lifespan. However, it remains unknown if A{beta} is inherently toxic or if it triggers toxic downstream pathways that lead to neurodegeneration. Here, we describe a novel, and previously unidentified, protective role of intracellular laminin chain accumulation. Despite high A{beta} levels, over-expression of the extracellular matrix protein subunit Laminin B1 (LanB1) resulted in a robust rescue of toxicity, highlighting a potential protective mechanism of resistance to A{beta}. Over-expression of other Laminin subunits and a Collagen IV subunit also significantly rescued A{beta} toxicity, while combining LanB1 with these subunits led to an even larger rescue. Imaging revealed that LanB1 was retained in the ER but had no effect on the secretion of A{beta} into the extracellular milieu. LanB1 rescued toxicity independently of the IRE1/XBP1-mediated branch of the ER stress response. Interestingly, over-expression of ER-targeted GFP also rescued A{beta} toxicity, indicating a potentially broader benefit of ER protein retention. Finally, in proof-of-principle lentiviral transduction experiments using murine organotypic hippocampal slice cultures, over-expression of mouse Lamb1 resulted in ER-retention in transduced cells, highlighting a conserved mechanism. Typically, retention of proteins in the ER is detrimental to cellular health, but in the context of neuronal A{beta} toxicity it may prove to be beneficial and a new therapeutic avenue for AD.