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

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 3 days 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.