Zebrafish: an emerging real-time model system to study Alzheimer's disease and neurospecific drug discovery

Abstract

Zebrafish (Danio rerio) is emerging as an increasingly successful model for translational research on human neurological disorders. In this review, we appraise the high degree of neurological and behavioural resemblance of zebrafish with humans. It is highly validated as a powerful vertebrate model for investigating human neurodegenerative diseases. The neuroanatomic and neurochemical pathways of zebrafish brain exhibit a profound resemblance with the human brain. Physiological, emotional and social behavioural pattern similarities between them have also been well established. Interestingly, zebrafish models have been used successfully to simulate the pathology of Alzheimer's disease (AD) as well as Tauopathy. Their relatively simple nervous system and the optical transparency of the embryos permit real-time neurological imaging. Here, we further elaborate on the use of recent real-time imaging techniques to obtain vital insights into the neurodegeneration that occurs in AD. Zebrafish is adeptly suitable for Ca²⁺ imaging, which provides a better understanding of neuronal activity and axonal dystrophy in a non-invasive manner. Three-dimensional imaging in zebrafish is a rapidly evolving technique, which allows the visualisation of the whole organism for an elaborate in vivo functional and neurophysiological analysis in disease condition. Suitability to high-throughput screening and similarity with humans makes zebrafish an excellent model for screening neurospecific compounds. Thus, the zebrafish model can be pivotal in bridging the gap from the bench to the bedside. This fish is becoming an increasingly successful model to understand AD with further scope for investigation in neurodevelopment and neurodegeneration, which promises exciting research opportunities in the future.

Fig. 1

Advantages of using zebrafish as an AD model

Fig. 2

Possible genetic manipulations in zebrafish: ‘forward genetic’ tools exist to create random mutations in the zebrafish genome. Several ‘reverse genetic’ methods are also in use to identify and characterise zebrafish genes of interest either by overexpression or by knocking it out. For inducing mutations researchers have used chemical mutagens like Ethyl-Nitroso Urea, viral vectors, transposon-based mutagenesis by conditional “gene trapping” and “gene breaking”, zinc finger nucleases, and the more recent one being, clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) systems, which provide the advantage of gene manipulation with ease and high efficiency, eliminating any unwanted off-target effect. Morpholinos, based on the antisense oligonucleotide gene knockdown technique, are the most regularly used reverse genetic tool for gene manipulation in zebrafish. They are designed in such a way that they bind to specific locations on the transcripts from genes of interest. The mode of action of morpholino can be by either blocking translation or interfering with the proper splicing of the exons. ‘Targeting Induced Local Lesions in Genomes’ (TILLING) method, has also been successfully adapted to zebrafish. Most recently the Transcription Activator-Like Effector Nucleases (TALENS) system is the most potent system for targeting genes in the zebrafish model