Chronic administration of a new therapeutic agent improves memory in a mouse model of Alzheimer’s disease with tau deposition.

Alzheimer’s disease (AD) is characterized clinically by progressive cognitive decline, eventually resulting in death, usually within 10 years of diagnosis. It is estimated that there are currently more than 18 million people worldwide with AD, and the number of affected individuals is projected to double by 2025. Abnormal tau hyperphosphorylation and its accumulation into intra-neuronal neurofibrillary tangles are linked to neurodegeneration in Alzheimer’s disease and similar tauopathies. One strategy to reduce tau accumulation could be through pharmacotherapeutics. The aim of this study was to test the effects of a chronic administration of a new therapeutic agent in a mouse model of tau deposition (Tg4510 mice) for effects on cognitive impairments and tau pathology in the brain. Tg4510 mice, carrying a transgene for human four-repeat tau with the P301L mutation (4R0N tauP301L) as well as a transgene for the calcium/calmodulin-dependent protein kinase type II (CAMK-II) tetracycline controlled transactivator protein were used. The human P301L mutation is associated with an autosomal dominantly inherited dementia referred to as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Mice (Tg4510; n=12 per group, balanced with respect to gender and litter) received test agent or control (vehicle) treatment into rodent chow diet for oral delivery during 3 months. A cohort of 12 untreated non-transgenic mice (FVB/129S F1 hybrid background) was used to measure baseline behavioral performance and glial activation measurements. All animals were 3 months old at the start of the study. Mice were maintained on a twelve-hour light/dark cycle. Water and food were provided ad libitum throughout the experiment. 2 weeks before the termination of the study, the mice were subjected to behavioral testing including open field, Y maze, radial arm water maze (RAWM) and novel object recognition by an observer blind to the treatment/genotype of the mice in order to evaluate learning, memory and general activity. Mice were euthanized with Somnasol®. Blood was drawn by cardiac puncture. Brains were collected following transcardial perfusion with 0.9% normal saline solution. Brains were sectioned with a freezing microtome and free-floating sections were stained for various molecular forms of tau. Differences between treatment conditions were assessed statistically using two-way ANOVA or student t-test when appropriate, with StatView version 5.0 (SAS institute Inc, Cary NC).

Tg4510 mice given the diet containing the test agent displayed a significant improvement in learning and memory during radial arm water maze since they were making significantly less errors when compared to Tg4510 under the control diet. As previously described, a genotype effect was evidenced in open field, rotarod, and novel object recognition, but no treatment effect. The diet containing the test agent had no effect on brain weight or body weight. Preliminary data seem to indicate no difference in tau pathology when assessed by western blotting or immunohistochemistry. Chronic administration of test agent in Tg4510 mice induced significant improvement in learning and memory during radial arm water maze that was associated with a reduction in tau oligomers in hippocampi homogenates. No effect of the diet was observed in other behavioral tests such as open field, rotarod and novel objects recognition. The diet had no effect on brain weight and body weight.