RESUMO
Amyloid ß (Aß) accumulation is a hallmark of Alzheimer's disease. In adult Drosophila brains, human Aß overexpression harms climbing and lifespan. It's uncertain whether Aß is intrinsically toxic or activates downstream neurodegeneration pathways. Our study uncovers a novel protective role against Aß toxicity: intra-endoplasmic reticulum (ER) protein accumulation with a focus on laminin and collagen subunits. Despite high Aß, laminin B1 (LanB1) overexpression robustly counters toxicity, suggesting a potential Aß resistance mechanism. Other laminin subunits and collagen IV also alleviate Aß toxicity; combining them with LanB1 augments the effect. Imaging reveals ER retention of LanB1 without altering Aß secretion. LanB1's rescue function operates independently of the IRE1α/XBP1 ER stress response. ER-targeted GFP overexpression also mitigates Aß toxicity, highlighting broader ER protein retention advantages. Proof-of-principle tests in murine hippocampal slices using mouse Lamb1 demonstrate ER retention in transduced cells, indicating a conserved mechanism. Though ER protein retention generally harms, it could paradoxically counter neuronal Aß toxicity, offering a new therapeutic avenue for Alzheimer's disease.