O3‐06‐02: Toll‐like receptor 9 ligand CpG ODN as a new highly effective agent for prevention and/or treatment of Alzheimer's disease

Manipulation of the immune system is becoming a promising treatment approach for Alzheimer's disease (AD). However, when this approach was tried in humans, in contrast to results in AD animal models, encephalitis emerged as a significant form of toxicity in some patients. Vaccination studies have so far mainly targeted the adaptive immune system. Our research group postulated stimulation of the innate immune system as possible alternative method for ameliorating AD related pathology, without associated toxicity. Our prior work in prion disease, suggested that this could be done effectively via Toll-like receptor 9 (TLR9). To assess the utility of TLR 9 agonist CpG ODN to stimulate the innate immune system and prevent AD pathology in a mouse model. Female Tg2576 mice were injected with either the TLR9 agonist type B CpG oligodeoxynucleotide 1826 or vehicle beginning at 6 weeks of age, and once a month thereafter for a total of 14 injections. Controls were non-transgenic C57BL/6 x SJL mice injected with vehicle on the same schedule. At the age of sixteen months, the mice were subjected to behavioral testing. No difference between Tg groups was found in any of the locomotor parameters. CpG treatment led to working memory improvement in APP Tg2576 mice as indicated by radial arm maze testing (two-way ANOVA p = 0.019, post-hoc Tg-CpG vs Tg-vehicle, p = 0.026). In evaluating the efficacy of CpG ODN peripheral administration in AD mice, we found that stimulation of TLR9 signaling led to 66%(p = 0.0001) reduction in cortical and 59% (p = 0.002) reduction in hippocampal amyloid burden compared to vehicle treated Tg animals. This remarkable reduction of amyloid burden was paralleled by a reduction in the numbers of activated microglia and astrocytes. When analyzed separately, we observed a significant decrease in vascular amyloid burden without any evidence of increased cerebral microhemmorhages. Furthermore, treatment with CpG ODN was highly effective at reducing the brain Aβ levels along with Aβ oligomers. These results validate the feasibility of TLR9 ligand CpG ODN currently in clinical trials for a variety of other diseases as a new highly effective agent for the prevention and/or treatment of AD.