Knockdown of Amyloid Precursor Protein in Zebrafish Causes Defects in Motor Axon Outgrowth

Ping Song,Sanjay W. Pimplikar,Colin Combs

doi:10.1371/journal.pone.0034209

Ping Song, Sanjay W. Pimplikar + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0034209

Copy DOI

Journal: PloS one	Publication Date: Apr 24, 2012
Citations: 43	License type: CC BY 4.0

Affiliation: Cleveland Clinic Lerner College of Medicine

Abstract

Amyloid precursor protein (APP) plays a pivotal role in Alzheimer’s disease (AD) pathogenesis, but its normal physiological functions are less clear. Combined deletion of the APP and APP-like protein 2 (APLP2) genes in mice results in post-natal lethality, suggesting that APP performs an essential, if redundant, function during embryogenesis. We previously showed that injection of antisense morpholino to reduce APP levels in zebrafish embryos caused convergent-extension defects. Here we report that a reduction in APP levels causes defective axonal outgrowth of facial branchiomotor and spinal motor neurons, which involves disorganized axonal cytoskeletal elements. The defective outgrowth is caused in a cell-autonomous manner and both extracellular and intracellular domains of human APP are required to rescue the defective phenotype. Interestingly, wild-type human APP rescues the defective phenotype but APPswe mutation, which causes familial AD, does not. Our results show that the zebrafish model provides a powerful system to delineate APP functions in vivo and to study the biological effects of APP mutations.

Highlights

Amyloid precursor protein (APP) has been a focus of intense investigation because of its central role in Alzheimer’s disease (AD) pathogenesis [1,2,3]
Zebrafish embryos co-injected with full length human APP695 rescued the APPb morphant axonal outgrowth phenotype of motor neurons Vp and VII. (C) Embryos co-injected with hAPP695 rescued the defective phenotype of motor axons in the spinal cord in APPb morphant embryos
Embryos co-injected with APPb morpholino (APPb-morpholino oligonucleotides (MOs)) and hAPP695 mRNA had a rescued phenotype compared to the morphant group

Summary

Introduction

Amyloid precursor protein (APP) has been a focus of intense investigation because of its central role in Alzheimer’s disease (AD) pathogenesis [1,2,3]. It is a ubiquitously expressed, single-pass transmembrane protein that is constitutively processed into multiple smaller fragments [4]. Previous in vitro studies suggested that APP plays a role in cell migration and neuronal extension [9]. Combined deletion of APP and APLP2 results in postnatal lethality and a recent study showed that sAPPb (soluble ectoplasmic peptide produced by BACE cleavage) failed to rescue the lethality and neuromuscular synapse defects in double-KO mice [11]

Methods

Results

Conclusion