FTY720 Attenuates Infection-Induced Enhancement of Aβ Accumulation in APP/PS1 Mice by Modulating Astrocytic Activation.

Abstract

It is well established that infection has a significant detrimental effect on patients with Alzheimer's disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-β (Aβ) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amyloid pathology and deterioration of cognitive function. These changes are against a backdrop of an age- and AD-related increase in susceptibility to infection. Here we set out to determine whether FTY720, a molecule that binds sphingosine-1-phosphate (S1P) receptors and with known immunosuppressant effects mediating its therapeutic action in multiple sclerosis (MS), might modulate the impact of infection in a mouse model of AD. Transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice) and their littermates were/were not infected with Bordetella pertussis and were treated orally with FTY720 or vehicle beginning 3days before infection. Infection increased astrocytic activation and enhanced blood brain barrier (BBB) permeability and these changes were attenuated in FTY720-treated B. pertussis-infected mice. Significantly, infection increased Aβ containing plaques and soluble Aβ and these infection-related changes were also attenuated in FTY720-treated B. pertussis-infected mice. The data suggest that this effect results from an FTY720-induced increase in Aβ phagocytosis by astrocytes. FTY720 did not impact on genotype-related changes in the absence of an infection indicating that its potential usefulness is restricted to reducing the impact of acute inflammatory stimuli in AD.