Effects of the spi1a gene on Alzheimer's disease-related phenotypes in a zebrafish model

Genome-wide sequence analysis has identified the SPI1 gene as a genetic risk factor for Alzheimer's disease (AD). SPI1 encodes the PU.1 protein, which plays a critical role in microglial development and immune responses, primarily studied in mouse models. However, no studies have yet reported the impact of the SPI1 gene on AD-related phenotypes in zebrafish. Therefore, this study utilized CRISPR/Cas9 gene editing to generate spi1a knockout zebrafish mutants, investigating the effects of spi1a loss-of-function on AD-associated phenotypes. The results showed that spi1a knockout led to reduced locomotor activity and increased brain cell apoptosis in larvae, while working memory, acetylcholinesterase (AChE) activity and Aβ1–42 levels remained unchanged. In contrast, adult spi1a knockout zebrafish exhibited significant cognitive decline, upregulated apoptosis-related genes, elevated AChE activity and increased Aβ1–42 accumulation. Transcriptomic analysis further revealed that spi1a knockout altered the expression of multiple AD-related genes and affected immune and inflammation-related signaling pathways. In conclusion, spi1a deficiency induced AD-like phenotypes in adult zebrafish. This study demonstrates the role of spi1a in modulating AD-related phenotypes in both larval and adult zebrafish, providing crucial insights into AD pathogenesis and establishing a valuable model for future high-throughput drug screening and therapeutic development.