Determine the direct effect of novel TLR9 innate immune system stimulation on tau pathology

While a predominant number of treatment approaches for Alzheimer's Disease have focused on the reduction of amyloid beta plaques, there has been concerted shift to also target tau pathology, the other major pathological marker of AD. There is no current treatment for AD, however profound efforts have been made in developing an immunotherapy approach for AD. We have focused on activating Toll-like receptor 9 (TLR9), a stimulatory receptor of the innate immune system, in attempts to ameliorate the immune system’s dysfunctional clearance. Our earlier studies revealed that stimulation of the innate immunity via TLR9 agonist, CpG ODN, in 3xTg-AD mice can alleviate all pathological hallmarks of AD (Ab, tau, CAA) and improve behavioral deficits without toxicity. Given the importance of tau related pathology, we designed an experiment to more directly determine the effect of CpG-ODN on tau pathology. This was done through rTg4510 mice, a tauopathy mouse model which develops robust forebrain tangle pathology without concurrent amyloid pathology.

The rTg4510 mice were injected with either the TLR9 agonist Class B CpG-ODN or saline at monthly intervals (3 to 11 months of age). After the treatment period, histological and biochemical analyses (IHC, WB) were performed.  Peripheral immune response analyses (Th1/Th2 Luminex technology) are underway.

Histological evaluation of CpG-ODN effect on hippocampal and cortical brain regions revealed region specific reductions in PHF1 and MC1 immunoreactivity in CpG-ODN treated animals. Western blot analyses showed a significant reduction in total PHF1 phospho-tau levels in the CpG-ODN-treated group in comparison to the saline-treated animals.

Overall, the present findings, together with our earlier research, demonstrate promising preclinical evidence for the potential use of TLR9 ligand CpG ODN as a disease modifying drug for Alzheimer’s disease and other tau related dementias.