| dc.description.abstract | Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder characterized by memory loss and cognitive decline, with loss of global functioning over time eventually leading to death. At the molecular level, it is recognised that the aberrant aggregation and accumulation of both β-amyloid 1-42 into fibrillar plaques, and hyperphosphorylated tau into neurofibrillary tangles are the two major contributors to the axonal degeneration, synapse loss and eventual neuronal cell death that are characteristic of disease pathology. Current therapies for AD are symptomatic and seek to redress the neurotransmitter imbalances that contribute to memory-cognitive deficits, but cannot stop or reverse disease progression. More recently, CNS neuroinflammation in AD has been recognised as a third major branch of pathology contributing to neuronal cell death. Chronic activation of glial cells confers a pro-inflammatory phenotype in the CNS, propagating the release of pro-inflammatory cytokines and further glial activation. Therefore, immune modulation in the CNS constitutes a promising therapeutic target for the amelioration of the inflammatory profile in AD. FTY720, an immunomodulatory pro-drug used for relapsing-remitting multiple sclerosis, is a potent sphingosine 1-phosphate receptor (S1PR) agonist. S1PRs have been found to be expressed on all major glial cell types, constituting a prime target for FTY720-mediated modulation of the activity of these cell types. We utilised the McGill-R-Thy1-APP rat model of AD to assess the effects of FTY720 on spatial memory and the neuroinflammatory profile of AD. At 6 months of age, rats were orally treated with 1mg/kg FTY720 for 6 months, before subjection to Morris Water Maze (MWM), Novel Object Localization (NOL) and Open Field (OF) behavioural assessments, with sacrifice at 12 months. FTY720 was found to improve spatial memory in AD animals in the MWM but not the NOL task, and no changes in locomotion or anxiety-like behaviour were observed in the OF. Amyloid precursor protein (APP) expression was found to be significantly increased in both the hippocampus and cerebellum, which was attenuated by FTY720. Western blot analysis of glial fibrillary acidic protein (GFAP), vimentin and ionized calcium-binding adaptor molecule 1 (Iba1) astrocyte and microglial markers in the hippocampus showed no significant difference in the expression levels of these proteins between wild-type (WT) and APP animals, and FTY720 also had no significant effect on their expression. Expression levels of myelin basic protein were found to be increased in WT animals with FTY720 treatment, but not in transgenics, while there was found to be no effect of genotype or treatment in myelin oligodendrocyte glycoprotein expression. Taken together, these results suggest that FTY720 can ameliorate behavioural aspects of AD in vivo but its effect on molecular indicators of reactive gliosis is | en |
