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FTY720 Attenuates Infection-Induced Enhancement of Aβ Accumulation in APP/PS1 Mice by Modulating Astrocytic Activation
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نویسنده
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McManus Róisín M. ,Finucane Orla M ,Wilk Mieszko M. ,Mills Kingston H. G. ,Lynch Marina A.
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منبع
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journal of neuroimmune pharmacology - 2017 - دوره : 12 - شماره : 4 - صفحه:670 -681
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چکیده
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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.
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کلیدواژه
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Astrocytes ,Alzheimer’s disease ,Blood brain barrier permeability ,Phagocytosis ,Amyloid-β ,FTY720
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آدرس
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Trinity College Dublin, Ireland, Trinity College Dublin, Ireland, Trinity College Dublin, Ireland, Trinity College Dublin, Ireland, Trinity College Dublin, Ireland
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Authors
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