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

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

doi:10.1038/s41467-018-04389-0

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

Nat Commun. 2018 Jul 30;9(1):2968. doi: 10.1038/s41467-018-04389-0.

Authors

Qing Yu^{1

2}, Yongfu Wang¹, Fang Du¹, Shijun Yan¹, Gang Hu¹, Nicola Origlia³, Grazia Rutigliano³, Qinru Sun¹, Haiyang Yu², James Ainge⁴, Shi Fang Yan¹, Frank Gunn-Moore⁵, Shirley ShiDu Yan⁶

Affiliations

¹ Department of Pharmacology and Toxicology and Higuchi Bioscience Center, University of Kansas, Lawrence, KS, 66047, USA.
² State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Cheng Du, China.
³ CNR, Institute of Neuroscience, 56124, Pisa, Italy.
⁴ School of Psychology and Neuroscience, University of St Andrews, St Mary's Quad Street, St Andrews, KY16 9JP, UK.
⁵ School of Biology, Medical and Biological Sciences Building, University of St Andrews, North Haugh Street, St Andrews, KY16 9TF, UK.
⁶ Department of Pharmacology and Toxicology and Higuchi Bioscience Center, University of Kansas, Lawrence, KS, 66047, USA. shidu@ku.edu.

Abstract

Endophilin 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adenosine Triphosphate / metabolism
Alzheimer Disease / genetics*
Amyloid beta-Peptides / genetics
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / genetics
Animals
Animals, Genetically Modified
Antioxidants / metabolism
Crosses, Genetic
Disease Models, Animal
Gene Expression Regulation*
Hippocampus / metabolism
Humans
Long-Term Potentiation
Mice
Mice, Transgenic
Mitochondria / metabolism
Neurons / metabolism
Neurotransmitter Agents / metabolism
Peptide Fragments / metabolism
Reactive Oxygen Species / metabolism
Synapses / metabolism
Synaptic Vesicles / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

APP protein, human
Adaptor Proteins, Signal Transducing
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Antioxidants
Neurotransmitter Agents
Peptide Fragments
Reactive Oxygen Species
SH3GL2 protein, human
endophilin A1 protein, mouse
Adenosine Triphosphate
p38 Mitogen-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding