Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Aβ accumulation

作者：Alim Muhammad, Ingrid Flores, Hong Zhang, Rui Yu, Agnieszka Staniszewski, Emmanuel Planel, Mathieu Herman, Lingling Ho, Robert A. Kreber, Lawrence S. Honig, Barry Ganetzky, Karen Duff, Ottavio Arancio, Scott A. Small · 发表于：Proceedings of the National Academy of Sciences · 年份：2008 · DOI：10.1073/pnas.0802545105 · 被引用次数：256 · 研究领域：Alzheimer's disease research and treatments、Genetics and Neurodevelopmental Disorders、Neuroscience and Neuropharmacology Research

Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Abeta peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Abeta aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.