Abstract
CX3CR1 is a chemokine receptor expressed on microglia that binds Fractalkine (CX3CL1) and regulates microglial recruitment to sites of neuroinflammation. Full deletion of CX3CR1 in mouse models of Alzheimer's disease have opposing effects on amyloid-β and tau pathologies raising concerns about the benefits of targeting CX3CR1 for treatment of this disease. Since most therapies achieve only partial blockade of their targets, we investigated the effects of partial CX3CR1 deficiency on the development and progression of amyloid-β deposition in the PS1-APP Alzheimer's mouse model. We generated PS1-APP mice heterozygous for CX3CR1 (PS1-APP-CX3CR1+/−) and analyzed these mice for Alzheimer's-like pathology. We found that partial CX3CR1 deficiency was associated with a significant reduction in Aβ levels and in senile-like plaque load in the brain as compared with age-matched PS1-APP mice. Reduced Aβ level in the brain was associated with improved cognitive function. Levels of the neuronal-expressed Aβ-degrading enzymes insulysin and matrix metalloproteinase 9, which are reduced in the brains of regular PS1-APP mice, were significantly higher in PS1-APP-CX3CR1+/− mice. Our data indicate that lowering CX3CR1 levels or partially inhibiting its activity in the brain may be a therapeutic strategy to increase neuronal Aβ clearance, reduce Aβ levels and delay progression of Alzheimer's-Like disease. Our findings also suggest a novel pathway where microglial CX3CR1 can regulates gene expression in neurons.
Highlights
Deposition of amyloid-β (Aβ) in the brain is one of the pathological hallmarks of Alzheimer’s disease (AD)
Aβ levels in the brain are regulated by several mechanisms: [1] the pathways that generate Aβ consisting of β-secretase and the γ-secretase complex [1]; [2] the enzymes that clear Aβ by means of degradation, such as neprilysin, insulysin (IDE), and matrix metalloproteinase 9 (MMP9) [2, 3]; [3] clearance of Aβ through phagocytosis by mononuclear phagocytes/microglia and astrocytes, and [4] transport across the blood brain barrier [4]
We show that partial CX3CR1 deficiency in PS1-APP-CX3CR1+/− mice is associated with significant reductions in the amount of Aβ [1-42] and [1-40] and the number of visible Aβ deposits in their brains compared to regular PS1-APP mice
Summary
Deposition of amyloid-β (Aβ) in the brain is one of the pathological hallmarks of Alzheimer’s disease (AD). CX3CR1 and its chemokine ligand fractalkine (CX3CL1) have been implicated in the recruitment of mononuclear phagocytes to sites of inflammation and injury [7, 10, 11] and play roles in the pathogenesis of several inflammatory conditions, including atherosclerosis [12, 13], neuropathic pain [14], and asthma [15]. In Alzheimer’s disease complete deletion of CX3CR1 in models of amyloid deposition reduced Aβ deposits and enhanced microglial Aβ phagocytic ability [16, 17]. These studies provided important insight on the role of CX3CR1 in AD and suggested that targeting CX3CR1 activity may be a therapeutic strategy to lower Aβ levels. It is possible to achieve partial inhibition of CX3CR1 activity pharmacologically, similar to what is observed in mice heterozygous for this receptor (CX3CR1+/−)
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