Authors: Lina Vandermeulen, Ivana Geric, Laura Fumagalli, Mohamed Kreir, Ashley Lu, Annelies Nonneman, Jessie Premereur, Leen Wolfs, Rafaela Policarpo, Nicola Fattorelli, An De Bondt, Ilse Van Den Wyngaert, Bob Asselbergh, Mark Fiers, Bart De Strooper, Constantin d’Ydewalle and Renzo Mancuso
Molecular Neurodegeneration, 24 April 2024
Scientists use Axion’s noninvasive Maestro MEA to assess the safety and potential off-target effects of antisense oligonucleotide (ASO) candidates.
Research has shown that microglia are important for maintaining brain homeostasis and also play a role in neurodegenerative diseases. Genetic variants in genes strongly expressed by microglia, such as Apolipoprotein E (APOE) and myeloid cells 2 (TREM2), are significant risk factors for Alzheimer's disease. In this study, scientists explore antisense oligonucleotides (ASOs) as a potential therapeutic strategy to modulate expression of these genes, using the Maestro Pro multielectrode array (MEA) system to assess the safety and off-target effects of APOE and TREM2 ASO candidates on rat primary neural cultures. Real-time monitoring on Maestro MEA showed that while TREM2 ASO did not affect electrophysiological phenotypes (including activity, bursting, and synchrony), APOE ASO treatment induced decreased firing, bursting, and synchrony at higher doses, indicative of potential hazardous sedative effects. Overall, the authors conclude that “our data reveal for the first time that APOE and TREM2 expression levels can be reduced with ASOs in human microglia in vitro and in vivo, and that leads to alterations in the phenotypic response of microglia to amyloid-β pathology,”—findings that may lead to new therapeutic approaches for neurodegenerative diseases.
