Effects of SPI1-mediated transcriptome remodeling on Alzheimer’s disease-related phenotypes in mouse models of Aβ amyloidosis

Byungwook Kim, Luke Child Dabin, Mason Douglas Tate, Hande Karahan, Ahmad Daniel Sharify, Dominic J. Acri, Md Mamun Al-Amin, Stéphanie Philtjens, Daniel Curtis Smith, H. R. Sagara Wijeratne, Jung Hyun Park, Mathias Jucker and Jungsu Kim ()
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Byungwook Kim: Indiana University School of Medicine
Luke Child Dabin: Indiana University School of Medicine
Mason Douglas Tate: Indiana University School of Medicine
Hande Karahan: Indiana University School of Medicine
Ahmad Daniel Sharify: Indiana University School of Medicine
Dominic J. Acri: Indiana University School of Medicine
Md Mamun Al-Amin: Indiana University School of Medicine
Stéphanie Philtjens: Indiana University School of Medicine
Daniel Curtis Smith: Indiana University School of Medicine
H. R. Sagara Wijeratne: Indiana University School of Medicine
Jung Hyun Park: Indiana University School of Medicine
Mathias Jucker: German Center for Neurodegenerative Diseases (DZNE)
Jungsu Kim: Indiana University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract SPI1 was recently reported as a genetic risk factor for Alzheimer’s disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-β (Aβ) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.

Date: 2024
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DOI: 10.1038/s41467-024-48484-x

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