A Review on Application of Zebrafish Disease Models, Neurobehavioral Phenotyping, and Biochemical Markers in Preclinical Screening for Alzheimer’s Disease

Review Article

Abstract

Preclinical evaluation of therapeutic candidates for Alzheimer's disease faces substantial attrition, largely arising due to high operational costs and translational limitations of traditional mammalian models. Danio rerio has gained prominence as a powerful alternative vertebrate system, offering high genetic homology, conserved neuroanatomy, transparent early development, and compatibility with high-throughput phenotypic screening. Diverse experimental approaches replicate distinct facets of neurodegeneration, encompassing pharmacological neurotoxins (scopolamine, aluminum chloride, okadaic acid, streptozotocin), synthetic amyloid-beta microinjections, and targeted genetic engineering (psen1/2, app, MAPT). Quantifiable behavioral paradigms, including spontaneous alternation assays, novel object recognition, inhibitory avoidance, and shoaling dynamics, reliably assess spatial navigation, declarative recall, associative learning, and social cohesion. Biochemical validation couples these functional outputs to neurochemical restoration by tracking acetylcholinesterase kinetics, reactive oxygen species accumulation, lipid peroxidation, endogenous antioxidant depletion, and pro-inflammatory signaling cascade suppression. Despite evolutionary distinctions in telencephalic lamination and teleost-specific gene duplications, integrating automated behavioral tracking with multi-omic and molecular endpoints establishes a robust translational bridge between in vitro assays and mammalian validation, accelerating the identification of disease-modifying neurotherapeutics