Overexpression of endophilin A1 exacerbates synaptic alterations in a mouse model of Alzheimer’s disease

• DOI: 10.1038/s41467-018-04389-0
• Publication Date: 2018-07-24T08:42:32Z
• Authors: Qing Yu; Yongfu Wang; Fang Du; Shijun Yan; Gang Hu; Nicola Origlia; Grazia Rutigliano; Qinru Sun; Haiyang Yu; James Ainge; Shi Fang Yan; Frank Gunn-Moore; Shirley ShiDu Yan
• Keywords: 570; Science; Long-Term Potentiation; NDAS; 610; Mice, Transgenic; Hippocampus; Article; Antioxidants; Animals, Genetically Modified; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; Adenosine Triphosphate; Alzheimer Disease; Animals; Humans; R2C; Crosses, Genetic; Adaptor Proteins, Signal Transducing; Neurons; Neurotransmitter Agents; 0303 health sciences; Adaptor Proteins, Signal Transducing; Adenosine Triphosphate; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Animals, Genetically Modified; Antioxidants; Crosses, Genetic; Disease Models, Animal; Hippocampus; Humans; Long-Term Potentiation; Mice; Mice, Transgenic; Mitochondria; Neurons; Neurotransmitter Agents; Peptide Fragments; Reactive Oxygen Species; Synapses; Synaptic Vesicles; p38 Mitogen-Activated Protein Kinases; Gene Expression Regulation; endophilin 1A; Amyloid beta-Peptides; Q; Peptide Fragments; Mitochondria; Disease Models, Animal; Gene Expression Regulation; RC0321; BDC; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry

AbstractEndophilin A1 (EP) is a protein enriched in synaptic terminals that has been linked to Alzheimer’s disease (AD). Previous in vitro studies have shown that EP can bind to a variety of proteins, which elicit changes in synaptic transmission of neurotransmitters and spine formation. Additionally, we previously showed that EP protein levels are elevated in AD patients and AD transgenic animal models. Here, we establish the in vivo consequences of upregulation of EP expression in amyloid-β peptide (Aβ)-rich environments, leading to changes in both long-term potentiation and learning and memory of transgenic animals. Specifically, increasing EP augmented cerebral Aβ accumulation. EP-mediated signal transduction via reactive oxygen species (ROS)/p38 mitogen-activated protein (MAP) kinase contributes to Aβ-induced mitochondrial dysfunction, synaptic injury, and cognitive decline, which could be rescued by blocking either ROS or p38 MAP kinase activity.