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P2‐067: WHAT WOULD BE THE LIKELY IMPACT OF AN INTERVENTION THAT SUCCESSFULLY PREVENTED NEOCORTICAL ACCUMULATION OF NEURITIC AMYLOID PLAQUES AND A HIGH BRAAK STAGE? THOUGHT EXPERIMENTS USING DATA FROM THE NUN STUDY (NS) AND THE HONOLULU‐ASIA AGING STUDY
Author(s) -
White Lon R.,
Edland Steven D.,
Hemmy Laura S.,
Flanagan Margaret E.,
Liu Catherine,
Feng Jing,
Himmer Elyssa K.,
Montine Thomas J.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.752
Subject(s) - dementia , senile plaques , cognitive decline , neurology , prodromal stage , stage (stratigraphy) , medicine , cognition , psychology , alzheimer's disease , pathology , audiology , neuroscience , disease , biology , paleontology
pathology; the other major pathological marker of Alzheimer’s Disease (AD). Our initial studies document that TLR9 signaling with the type B CpG ODN has a beneficial effect in 3xTg-AD mice with both plaque and tangle pathology without toxicity, suggesting that stimulating the innate immunity has the possible advantage of concurrently addressing both AD pathologies. Given the importance of tau related pathology, we felt it was critical to more precisely determine the effect of our novel approach in rTg4510 mice, a tauopathy mouse model which develops robust forebrain tangle pathology without concomitant Ab pathology. Methods: The rTg4510 mice were injected with either the TLR9 agonist class B CpG ODN or saline at monthly intervals (from 3 to 11 months of age). After the treatment the mice were subjected to behavioral testing. Histological analyses commenced upon completion of the behavioral protocol. Animals were continuously monitored for signs of toxicity.Results:Administration of CpGODNwas effective at improving spatial working memory evaluated using the closed field symmetrical maze in rTg4510 mice. No difference between groups was found in any of the locomotor parameters. 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. Although the effect on tau pathology was modest, our findings confirmed that this type of immunomodulation has beneficial effects on tau related pathology, in contrast to number of other prior innate immunity stimulation approaches. Biochemical assessments of tau levels are underway. No differences were noted in the extent of CD45 microgliosis and GFAP astrogliosis in CpG ODN-treated animals compared to controls, at the end of the treatment. In addition, we have preliminary data showing that acute injection of CpG ODN leads to an induction of favorable microglia/macrophage activation in rTg4510 mice. Further characterization of immune responses is ongoing. Conclusions:Overall, the present findings, together with our earlier research, represent essential preclinical evidence validating the feasibility of TLR9 ligand CpG ODN as a disease modifying drug for AD.