O4‐02‐02: TARGETING THE ALZHEIMER'S DISEASE‐ASSOCIATED RISK GENE, TREM2, WITH ANTISENSE OLIGONUCLEOTIDES

Genetic variants within the TREM2 gene show strong association with increased Alzheimer's disease (AD) risk. To enhance understanding of TREM2 loss, mice haploinsufficient or null for TREM2 have been crossed with amyloid beta (Aβ) depositing mouse models, yielding both positive and negative effects of TREM2 reduction on Aβ deposition. When crossed to mutant tau P301S mice, TREM2 deletion protected mice from neuronal degeneration. While these ongoing studies have identified important relationships between TREM2, microglia, and AD pathology, they are challenging to interpret in the context of disease progression and have the added complication of TREM2 absence from birth in both the CNS and periphery. We hypothesize that TREM2 reduction in AD models will be beneficial and lack adverse effects on tau, providing support for application of a TREM2 lowering strategy for patients. We developed antisense oligonucleotides (ASOs) that potently lower TREM2 mRNA throughout the brain. ASOs were administered to the lateral ventricle via a single bolus injection in APP/PS1 and TauP301S mice at 10 and 7 months of age, respectively. One month later, APP/PS1 mice were assessed for plaque deposition and microglial responses, and TauP301S mice were analyzed for tau pathology. TREM2-targeted ASO treatment in APP/PS1 mice substantially decreased TREM2 mRNA compared to control ASO treatment across multiple brain regions (p<0.01). When evaluated for Aβ, ASO-mediated TREM2 knockdown significantly reduced Aβ plaque deposition (p<0.001) and attenuated microglial association around plaque deposits (p<0.001). Treatment of TauP301S mice with TREM2-targeted ASO robustly decreased TREM2 mRNA (p<0.001) and was associated with significantly less phosphorylated tau reactivity within the hippocampus (p<0.05). These results confirm a role for TREM2 in mediating plaque deposition and tau phosphorylation and suggest that TREM2 lowering reduces pathological markers of neurodegeneration. While these data are seemingly contradictory to the presumption that TREM2 genetic variants confer a loss of function, we believe an ASO approach allows us to understand the timing of TREM2 action throughout disease progression, which may involve a time- or location-dependent role for TREM2. Overall, ASOs that target TREM2 will be highly informative on TREM2-mediated AD pathogenesis and may be effective at modulating disease.