Ascidians: an invertebrate chordate model to study Alzheimer’s disease pathogenesis

Abstract

SUMMARY Here we present the ascidian Ciona intestinalis as an alternative invertebrate system to study Alzheimer’s disease (AD) pathogenesis. Through the use of AD animal models, researchers often attempt to reproduce various aspects of the disease, particularly the coordinated processing of the amyloid precursor protein (APP) by α-, β- and γ-secretases to generate amyloid beta (Aβ)-containing plaques. Recently, Drosophila and C. elegans AD models have been developed, exploiting the relative simplicity of these invertebrate systems, but they lack a functional Aβ sequence and a β-secretase ortholog, thus complicating efforts to examine APP processing in vivo. We propose that the ascidian is a more appropriate invertebrate AD model owing to their phylogenetic relationship with humans. This is supported by bioinformatic analyses, which indicate that the ascidian genome contains orthologs of all AD-relevant genes. We report that transgenic ascidian larvae can properly process human APP695 to generate Aβ peptides. Furthermore, Aβ can rapidly aggregate to form amyloid-like plaques, and plaque deposition is significantly increased in larvae expressing a human APP695 variant associated with familial Alzheimer’s disease. We also demonstrate that nervous system-specific Aβ expression alters normal larval behavior during attachment. Importantly, plaque formation and alterations in behavior are not only observed within 24 hours post-fertilization, but anti-amyloid drug treatment improves these AD-like pathologies. This ascidian model for AD provides a powerful and rapid system to study APP processing, Aβ plaque formation and behavioral alterations, and could aid in identifying factors that modulate amyloid deposition and the associated disruption of normal cellular function and behaviors.

Modeling human neurodegenerative diseases in transgenic systems

“…For example, human APP 695 has been expressed in the ascidian non-vertebrate chordate Ciona intestinalis, where it was observed to be processed into A peptides in the nervous system resulting in formation of amyloid plaques and altered larval behavior (Virata and Zeller 2010). Clearly, eVorts to develop models of human neurodegenerative disease can be expected to continue in traditional as well as non-traditional species.…”

A pipeline for the systematic identification of non-redundant full-ORF cDNAs for polymorphic and evolutionary divergent genomes: Application to the ascidian Ciona intestinalis

“…Ascidians have been proposed as a model for human disease ( Virata and Zeller, 2010 ). This is, in part, based on their intermediate evolutionary distance between human and the more tractable but phylogenetically distant model system of the fly and the worm.…”

“…As expected from their phylogenetic vicinity to vertebrates, ascidian proteins may be active when expressed in vertebrate systems ( Davis and Smith, 2002; Marcellini et al, 2003 ). Finally, ascidians are promising organisms to understand the molecular mechanisms underlying human pathologies ( Virata and Zeller, 2010 ) and tissue regeneration ( Jeffery, 2015; Rinkevich et al, 2013 ).…”

Efficient genome editing using CRISPR‐Cas‐mediated homology directed repair in the ascidian Ciona robusta

“…The ability to precisely edit the genomes of a variety of organisms has greatly expanded the usefulness of these systems as models for human development and disease (Cardi, D'Agostino, & Tripodi, ; Chen et al, ; Singh, Braddick, & Dhar, ). Ascidians are gaining prominence as excellent models for examining a wide variety of biological problems including regeneration (Spina, Guzman, Zhou, Kosik, & Smith, ), Alzheimer's studies (Virata & Zeller, ), and climate change research (Lopez et al, ). The ascidian embryo also provides a rapid and useful system for the analysis of complex regulatory elements (Farley et al, ; Kusakabe, ; Satou & Imai, ).…”