EXPLORING THE USE OF NOVEL ASOS AGAINST TAU IN DOWN SYNDROME BRAIN PATHOLOGY

Considering the suggested mediating role of Tau in Alzheimer’s disease (AD) and the similarities between Down Syndrome (DS) and AD brain pathologies, we designed, tested and validated novel antisense oligonucleotides against Tau (Tau-ASOs) in DS brain. We used different chemical modifications in the design, while targeting both total Tau or 4R-Tau-specific mRNA. We firstly tested the Tau-ASOs in cell lines and primary neurons, later moving for in vivo validation in WT mice. Then, the most potent Tau-ASOs were tested as possible therapeutic strategy in Ts65Dn mouse model of DS.
Selected Tau-ASOs (tTau-ASO, 4rTau-ASO) were administered via i.c.v. at a concentraction of 15µM in Ts65Dn mice (12-month-old, male/female). Six weeks after treatment, behavioral screening started, followed by brain collection for molecular/neurostructural analysis (9 weeks post-administration). Behavioral analysis revealed that both Tau-ASOs were efficient reverting memory deficits observed in MWM, as well as some reversion in anxiety-like behavior, without reverting hyperactivity. Molecular analysis revelead that both Tau-ASOs show high efficacy reducing hippocampal and cortical levels of Tau mRNA and protein. This reduction showed positive impact in DG neuronal morphology (tTau-ASO) and spine density (4rTau-ASO). Proteomic analysis revealed that tTau-ASO lead to major proteomic changes in Ts65Dn brain, while 4rTau-ASO had a more specific profile, but both modulated pathways related to neuroplasticity/neurotransmitter signaling.
Our data provide the first preclinical evidence of therapeutic potential of ASOs against Tau in DS brain pathology, highlighting the promising use of innovative RNA-based therapeutic platform of ASOs in diverse Tau-related brain pathologies.