Catterson, J.H., Minkley, L., Aspe, S., Judd-Mole, S., Moura, S., Dyson, M.C., Rajasingam, A., Woodling, N.S., Atilano, M.L., Ahmad, M., Durrant, C.S., Spires-Jones, T.L., Partridge, L. (2023). Protein retention in the endoplasmic reticulum rescues Aβ toxicity in Drosophila.  Neurobiol. Aging 132(): 154--174.

FBrf0257957

Research paper

Amyloid β (Aβ) accumulation is a hallmark of Alzheimer's disease. In adult Drosophila brains, human Aβ overexpression harms climbing and lifespan. It's uncertain whether Aβ is intrinsically toxic or activates downstream neurodegeneration pathways. Our study uncovers a novel protective role against Aβ toxicity: intra-endoplasmic reticulum (ER) protein accumulation with a focus on laminin and collagen subunits. Despite high Aβ, laminin B1 (LanB1) overexpression robustly counters toxicity, suggesting a potential Aβ resistance mechanism. Other laminin subunits and collagen IV also alleviate Aβ toxicity; combining them with LanB1 augments the effect. Imaging reveals ER retention of LanB1 without altering Aβ secretion. LanB1's rescue function operates independently of the IRE1α/XBP1 ER stress response. ER-targeted GFP overexpression also mitigates Aβ 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 Aβ toxicity, offering a new therapeutic avenue for Alzheimer's disease.

PMC10940166 (PMC) (EuropePMC)