Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice

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.

A new genetic strategy for targeting microglia in development and disease

“…Finally, Cx3cr1-EGFP, -Cre and -CreER mouse lines are haploinsufficient for Cx3cr1, as they were designed such that the EGFP , Cre or CreER coding regions replace the endogenous Cx3cr1 coding region. There is evidence that Cx3cr1 haploinsufficiency affects microglial function ( Hickman et al, 2019 ; Lee et al, 2010 ; Rogers et al, 2011 ), so these lines should be used with this caveat in mind.…”

Microglia in Alzheimer’s Disease in the Context of Tau Pathology

“…These findings pose the question as to why the absence of CX3CR1 promotes the phagocytosis of Aβ and not of tau. One possibility is that the absence of CX3CR1 signaling enhances the synthesis of Aβ receptors and enzymes that degrade this peptide [ 244 ]. In turn, this pathway may block those corresponding to tau, thus having opposite effects on each pathology.…”

Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration

“…Hence, altered CX3CL1/CX3CR1 signaling during aging could underlie neurogenesis impairments (reviewed in [201]). In this regard, CX3CR1 depletion in animal models of AD significantly reduces AD-related pathology by enhancing microglial phagocytic ability [202][203][204].…”