The localization of amyloid precursor protein to ependymal cilia in vertebrates and its role in ciliogenesis and brain development in zebrafish

Jasmine Chebli,Alexandra Abramsson,Brigitta Edeman,Tammaryn Lashley,Maryam Rahmati,Henrik Zetterberg,Anders Oldfors

doi:10.1038/s41598-021-98487-7

Abstract

Amyloid precursor protein (APP) is expressed in many tissues in human, mice and in zebrafish. In zebrafish, there are two orthologues, Appa and Appb. Interestingly, some cellular processes associated with APP overlap with cilia-mediated functions. Whereas the localization of APP to primary cilia of in vitro-cultured cells has been reported, we addressed the presence of APP in motile and in non-motile sensory cilia and its potential implication for ciliogenesis using zebrafish, mouse, and human samples. We report that Appa and Appb are expressed by ciliated cells and become localized at the membrane of cilia in the olfactory epithelium, otic vesicle and in the brain ventricles of zebrafish embryos. App in ependymal cilia persisted in adult zebrafish and was also detected in mouse and human brain. Finally, we found morphologically abnormal ependymal cilia and smaller brain ventricles in appa−/−appb−/− mutant zebrafish. Our findings demonstrate an evolutionary conserved localisation of APP to cilia and suggest a role of App in ciliogenesis and cilia-related functions.

Highlights

Amyloid precursor protein (APP) is expressed in many tissues in human, mice and in zebrafish
We found that the ependymal cilia in the region of interest (ROI) were significantly longer in appa−/−appb−/− mutants compared with wild-type larvae (Fig. 7), which was confirmed by frequency distribution (Supplementary file 5)
We show that App localizes to different non-motile and motile cilia in zebrafish larvae including the stereo- and kinocilia of the otic vesicle, motile cilia of olfactory sensory neurons in the olfactory epithelium, and cilia of the ependymal cells lining the brain ventricles

Summary

Introduction

Amyloid precursor protein (APP) is expressed in many tissues in human, mice and in zebrafish. Whereas the localization of APP to primary cilia of in vitro-cultured cells has been reported, we addressed the presence of APP in motile and in non-motile sensory cilia and its potential implication for ciliogenesis using zebrafish, mouse, and human samples. We report that Appa and Appb are expressed by ciliated cells and become localized at the membrane of cilia in the olfactory epithelium, otic vesicle and in the brain ventricles of zebrafish embryos. We found that the zebrafish App homologues are expressed by ciliated cells and become localized at the membrane of cilia in the otic vesicle, the nasal epithelium, and the brain ventricles of zebrafish embryos. We show that zebrafish embryos with mutations in both app paralogues (appa−/−appb−/−) have morphologically abnormal ependymal cilia and smaller brain ventricles compared with wild-type siblings

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Conclusion