Overexpression of endophilin A1 exacerbates synaptic alterations in a mouse model of Alzheimer\u2019s disease

Qing Yu,Nicola Origlia,Frank Gunn-Moore,Qinru Sun,Shijun Yan,Grazia Rutigliano,James Ainge,Yongfu Wang,Shi Fang Yan,Shirley Shidu Yan,Fang Du,Gang Hu,Haiyang Yu

doi:10.1038/s41467-018-04389-0

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.

Highlights

Endophilin A1 (EP) is a protein enriched in synaptic terminals that has been linked to Alzheimer’s disease (AD)
We showed that EP levels were higher in Amyloid-β peptide (Aβ)-rich brains from transgenic (Tg) AD mice again when compared to non-Tg control mice[28], suggesting that EP may potentially be an important intracellular player in the synaptic alterations detected in AD pathogenesis
In view of that EP has a raised expression in the brains of AD patients[28] and Tg mice with neuronal overexpression of a mutant human form of amyloid precursor protein (APP) (Tg mAPP, APPSwInd, J-20 line) driven by the platelet-derived growth factor β-chain promoter at 9–10 months of age (Supplementary Fig. 1a, b), we sought to develop a model system in which neuronal expression of EP would be exaggerated so that consequences of EP-dependent signaling in Aβ-rich environment could be established

Summary

Introduction

Endophilin A1 (EP) is a protein enriched in synaptic terminals that has been linked to Alzheimer’s disease (AD). Other studies indicate that loss of EP function in mice leads to neuronal dysfunction under normal physiological condition[21,22], and its expression can control glutamate release[23] and affects dendritic spine formation[19]. We showed that EP levels were higher in Aβ-rich brains from transgenic (Tg) AD mice again when compared to non-Tg control mice[28], suggesting that EP may potentially be an important intracellular player in the synaptic alterations detected in AD pathogenesis. We generated and characterized Tg mice overexpressing EP in neurons Using this genetically manipulated neuronal EP mouse model and a neuronal culture system with an Aβ-enriched environment, we have comprehensively analyzed the effects of neuronal EP on Aβ-induced abnormalities in synaptic neurotransmission and plasticity, synaptic density, and the altered learning and memory capabilities.

Methods

Results

Conclusion