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 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.

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…FTY720 reduced the number of cells positive for reactive A1 astrocytic markers glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100β) in multiple rodent models, including in a model of familial AD [45,51], cuprizone-induced demyelination [48], MS [50,61,82], Huntington's disease (HD) [84], Status epilepticus (SE) [54], and models of infection [85], stroke [86], ICH [47], Pentylenetetrazol (PTZ)-induced kindling [56], and maternal inflammation [87] as well as wild-type rodents [88]. In contrast, FTY720-treated immortalized astrocytes displayed increased release of the astrocyte-secreted protein GM-CSF [89], whereas LPS-stimulated primary astrocytes decreased GM-CSF release following treatment with FTY720 [65].…”

Exercise-Induced Modulation of Neuroinflammation in Models of Alzheimer’s Disease

“…With respect to astrocytes, AD-associated neuroinflammation is accompanied by reactive astrogliosis, the morphological and functional change seen in astrocytes in response to CNS injury or damage [ 90 ]. This has been repeatedly demonstrated in the APP/PS1 mouse [ 91, 92 ]. During this process, astrocytes are activated and undergo hypertrophy and/or proliferation [ 93 ] that can be identified by increased expression of glial fibrillary acidic protein (GFAP) [ 94 ], an intermediate filament protein of the astrocytic cytoskeleton.…”

Fingolimod Affects Transcription of Genes Encoding Enzymes of Ceramide Metabolism in Animal Model of Alzheimer’s Disease

“…In the same time, fingolimod reduced Aβ 42 plaque density and the total level of Aβ 42 [77]. The mechanism of Aβ accumulation may be augmented by proinflammatory environment in the diseased brain, which is suggested to impair Aβ clearance by astrocytes [78]. Mice overexpressing AβPP and presenilin 1 display activated local astroglia and microglia, infiltration of peripheral macrophages and natural killer cells [79].…”

“…Mice overexpressing AβPP and presenilin 1 display activated local astroglia and microglia, infiltration of peripheral macrophages and natural killer cells [79]. Infections, susceptibility to which rises in old age, are noted to accelerate the cognitive deterioration of AD patients [80] and to increase Aβ burden in animal models [78]. FTY720 has been shown to inhibit the infection-related activation of astrocytes, and to prevent accumulation of soluble and plaque Aβ in the mouse brain probably through stimulation of Aβ phagocytosis [78].…”