Experimental models for investigating hypoxia-inducible factor 1 modulation in neurodegeneration: A comprehensive review
Scientific research on modulation of hypoxia-inducible factor 1 (HIF-1) in neurodegeneration has increased considerably; however, selecting appropriate experimental models remains challenging for researchers due to the context-dependent nature of HIF-1 signaling and the diversity of available methodologies. Thus, this review aims to provide a comprehensive overview of the experimental models and methodologies adopted to study HIF-1 modulation in neurodegenerative diseases, focusing on their advantages and limitations as well as suitability for neurodegenerative research contexts. A thorough literature search was conducted across Scopus, PubMed, ScienceDirect, Web of Science, and Google Scholar, covering publications from January 2000 to June 2026. The review encompasses in vitro cellular systems, including primary neuronal and glial cultures, immortalized cell lines such as HT22, SH-SY5Y, and NSC34 cells, organotypic slice cultures, and oxygen–glucose deprivation models. In vivo approaches covered include transgenic mouse models (APP/PS1, 5xFAD, 3xTg-AD, SOD1G93A, microglial Hif1a knockout), chemically induced neurodegeneration models (MPTP, 6-OHDA, rotenone, α-synuclein, 3-nitropropionic acid, acrylonitrile, cobalt chloride, dimethyloxalylglycine), and cerebral ischemia models. Genetic model organisms including Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio are discussed for their unique utility in studying conserved HIF-1 pathways. Moreover, computational approaches are discussed. Major methodological considerations addressed include the balance between experimental design and physiological relevance, cell-type specificity, temporal dynamics of HIF-1 activation, and dose–response relationships for pharmacological modulators. Ultimately, integrating outcomes across multiple experimental systems coupled with rigorous experimental design will be essential for elucidating HIF-1-mediated pathophysiology and facilitating the translation of therapeutic strategies from bench to bedside.
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