APP‐dependent cell adhesion is regulated by GWAS genes
Julien Chapuis, Chloé NAJDEK, Audrey Coulon, Fanny Eysert, Benjamin Grenier‐Boley, Céline Bellenguez, Florie Demiautte, Philippe Amouyel, Julie Dumont, Devrim Kilinc, Jean‐Charles Lambert- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Thanks to Genome‐Wide Association Studies (GWAS), 75 susceptibility loci for Alzheimer’s disease (AD) have been identified (Bellenguez et al, Nat genetics. 2022). However, one of the greatest challenges resides in the understanding of the functional consequences of these genetic determinants. One of the main hypothesis would be that some of these genetic factors could be involved in APP metabolism and Aβ production. Indeed, even if numerous players of the APP metabolism have been characterized over the last 20 years, a large part of the is still unknown. Moreover, with more than 200 genes localized in the AD susceptibility loci, the classical approach, i.e., studying genes one by one, cannot be done in a timely manner. Therefore, we took advantage of Genome‐Wide siRNA screening using a High Content Screening (HCS) approach allowing a systematic functional assessment of human genes on APP metabolism.
Method
A HEK293 cell line stably over‐expressing a fluorescently‐tagged APP was transitory transfected in 384‐well plates with the human siGENOME siRNA library to silence every human gene. High content analysis was performed to automatically quantify (i) fluorescence intensities reflecting the intracellular accumulation of APP byproducts and (ii) cell‐cell interaction. Enrichment pathway analysis was performed to identify the pathways in which the modulators of APP are mainly involved.
Result
Expected GWAS‐defined genes were identified among the genes showing the stronger effects on APP metabolism (APP, ADAM10, SORL1). Moreover, we observed that a large portion of the GWAS‐defined genes are modulators of APP metabolism and are involved in cell adhesion signaling, including the genetic risk factors FERMT2 and Cass4. In our model, silencing of these genes was also able to modulate cell‐cell interaction, suggesting that APP‐dependent cell adhesion is regulated by GWAS‐defined genes.
Conclusion
Remarkably, many genetic risk factors of AD are involved in cell adhesion pathway, such as APP which has been shown to be involved in synaptic formation and plasticity. Since synaptic dysfunction and loss is one of the very early hallmarks of AD, our data suggest that beyond Aβ production, APP could impact AD process through an impairment of cell adhesion at the synaptic level.