Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS-AD-linked degenerative phenotypes in the Dp16 mouse model of Down syndrome.

INTRODUCTION: Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS-AD). Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS-AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11. METHODS: We investigated whether increasing APP gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS-AD mouse model was treated with a mouse App-specific antisense oligonucleotide (App-ASO) and Rab5-specific ASOs targeting Rab5a and Rab5b. RESULTS: App-ASO treatment normalized full-length APP (fl-APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways. Rab5-ASOs reduced RAB5 levels and restored endosomal Rab activity. Both ASO treatments mitigated DS-AD-linked pathologies. DISCUSSION: These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO-based strategies targeting APP or Rab5 to counteract DS-AD features. HIGHLIGHTS: App-ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice. Administration of Rab5-ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice. Both ASO treatments were well tolerated and mitigated APP-linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. App-ASO or Rab5-ASOs reversed established pathological phenotypes in Dp16 mice.