Associate Professor City University of Hong Kong, Hong Kong
Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, with early-onset familial forms strongly linked to APP gene dosage. Genomic duplication of the APP locus causes autosomal dominant early-onset AD, while individuals with Down syndrome (trisomy 21), who carry three copies of APP, consistently develop progressive AD with hallmark neuropathology. Despite the clear role of APP in disease pathogenesis, therapeutic strategies to normalize APP expression and mitigate its downstream effects remain limited. To address this gap, we tested antisense oligonucleotides (ASOs) targeting APP in human iPSC-derived cortical neurons from APP duplication and Trisomy 21 models. These ASOs effectively reduced APP protein levels, restoring endolysosomal and autophagy function—key processes disrupted in AD. Using ultrasensitive single-aggregate imaging, we demonstrated a significant reduction in intracellular and extracellular amyloid-β aggregates, a hallmark of AD pathology. These findings reveal the potential of APP-targeting ASOs as a novel therapeutic approach for AD caused by APP gene duplication, including monogenic and Down syndrome-associated AD. By leveraging human stem cell models, our work advances the field of RNA therapeutics, providing new insights into targeting genetic drivers of AD to prevent or slow disease progression.
