Alzheimer's disease (AD) is characterized neuropathologically by extracellular senile plaques composed of aggregated neurotoxic amyloid ß peptide (Aß) and intracellular neurofibrillary tangles (NFT) composed of abnormally hyperphosphorylated tau protein. Brain derived neurotrophic factor (BDNF) signaling, which is critical for hippocampal, cortical, and cholinergic neuron viability, is also abnormal in AD and may contribute to neurodegeneration. We propose to study the effects of Fingolimod an oral drug recently approved for the treatment of multiple sclerosis (MS) that targets both the peripheral and the central system. Fingolimod easily crosses the blood brain barrier (BBB) and inhibits production of proinflammatory cytokines from astrocytes and microglia, enhances synaptic strength and increase expression of neurotrophic factors. The neuroprotective effects of Fingolimod have been reported in models of epilepsy, spinal cord injury, cerebral ischemia and Rett syndrome. We will test the hypothesis that Fingolimod will have neuroprotective effects in mouse models of AD through its anti-inflammatory and BDNF-mediated neurotrophic effects. The effects of Fingolimod will be assessed in 2 complementary AD mouse models (5xFAD, 3xTg-AD) to determine the effects of Fingolimod on different aspects of AD pathology. 5xFAD mice, develop early neurodegeneration and massive accumulation of Aß; 3xTg-AD mice, develop both senile plaques and NFT. Aim is to determine the therapeutic effect of oral Fingolimod treatment (1 mg/kg/day) in 5xFAD mice treated from 1 to 8 months and 3xTg-AD mice treated from 1 to 18 months (n=10). These studies incorporate principals of rational pharmacology and cognitive evaluation combined with state-of- the-art neuropathological, neurochemical and gene-analysis techniques to define the therapeutic benefits of a novel wide-spectrum compound that crosses the blood-brain barrier in 2 different Alzheimer mouse models.