CX3CL1 Pathway as a Molecular Target for Treatment Strategies in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a scourge for patients, caregivers and healthcare professionals due to the progressive character of the disease and the lack of effective treatments. AD is considered a proteinopathy, which means that aetiological and clinical features of AD have been linked to the deposition of amyloid β (Aβ) and hyperphosphorylated tau protein aggregates throughout the brain, with Aβ and hyperphosphorylated tau representing classical AD hallmarks. However, some other putative mechanisms underlying the pathogenesis of the disease have been proposed, including inflammation in the brain, microglia activation, impaired hippocampus neurogenesis and alterations in the production and release of neurotrophic factors. Among all, microglia activation and chronic inflammation in the brain gained some attention, with researchers worldwide wondering whether it is possible to prevent and stop, respectively, the onset and progression of the disease by modulating microglia phenotypes. The following key points have been established so far: (i) Aβ deposition in brain parenchyma represents repeated stimulus determining chronic activation of microglia; (ii) chronic activation and priming of microglia make these cells lose neuroprotective functions and favour damage and loss of neurons; (iii) quiescent status of microglia at baseline prevents chronic activation and priming, meaning that the more microglia are quiescent, the less they become neurotoxic. Many molecules are known to modulate the quiescent baseline state of microglia, attracting huge interest among scientists as to whether these molecules could be used as valuable targets in AD treatment. The downside of the coin came early with the observation that quiescent microglia do not display phagocytic ability, being unable to clear Aβ deposits since phagocytosis is crucial for Aβ clearance efficacy. A possible solution for this issue could be found in the modulation of microglia status at baseline, which could help maintain both neuroprotective features and phagocytic ability at the same time. Among the molecules known to influence the baseline status of microglia, C-X3-chemokine Ligand 1 (CX3CL1), also known as Fractalkine (FKN), is one of the most investigated. FKN and its microglial receptor CX3CR1 are crucial players in the interplay between neurons and microglia, modulating the operation of some neural circuits and the efficacy and persistence of immune response against injury. In addition, CX3CL1 regulates synaptic pruning and plasticity in the developmental age and in adulthood, when it strongly impacts the hippocampus neurogenesis of the adult. CX3CL1 has an effect on Aβ clearance and tau phosphorylation, as well as in microglia activation and priming. For all the above, CX3CL1/CX3CR1 signalling has been widely studied in relation to AD pathogenesis, and its biochemical pathway could hide molecular targets for novel treatment strategies in AD. This review summarizes the possible role of CX3CL1 in AD pathogenesis and its use as a potential target for AD treatment.

The role of the CX3CL1/CX3CR1 axis as potential inflammatory biomarkers in subjects with periodontitis and rheumatoid arthritis: A systematic review

“… 29 , 30 , 31 , 32 , 33 , 34 However, in other diseases such as cancer, renal disease, neurological and cardiovascular disorders, HIV, and RA, its role has already been investigated. 17 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 33 The two objectives of this review will be discussed below.…”

“…FKN has a dual function by interacting with and binding to its receptor, the chemokine receptor 1 C‐X3‐C motif (CX3CR1), either as a cell adhesion molecule or a potent immune cell chemoattractant. 21 Thus, the CX3CL1/CX3CR1 axis is implicated in several important diseases such as atherosclerosis, 22 chronic kidney disease, 23 diffuse parenchymal diseases, 24 cancer, Alzheimer's disease, 25 and human immunodeficiency virus (HIV). 26 The role of CX3CL1/CX3CR1 in RA is already documented and can be consulted in other reviews.…”

Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer’s disease

“…Cell culture studies show that tau competes with fractalkine for uptake after binding to CX3CR1, and increased CX3CR1 expression in AD brains is associated with increased tau phosphorylation [ 24 , 57 ]. Disturbed fractalkine/CX3CR1 signaling may alter tau phagocytosis, enhance formation of neurofibrillary tangles and contribute to a neurotoxic transformation of microglia [ 58 , 59 ]. In line with this scenario, cases with stable tau pathology (A+/T+ or N+ and A−/T+ or N+) had sharply increased glial activation markers, including fractalkine.…”

CX3CL1 (Fractalkine)-CX3CR1 Axis in Inflammation-Induced Angiogenesis and Tumorigenesis

“…2011 [195]; Poniatowski et al 2017 [57]; Luo et al 2019 [196]; Bivona et al 2023 [197]; Nash et al 2015 [198]; Juliani et al 2021 [199] Bone marrow and immune tissue -The expression of CX3XR1 increases with the maturation of myeloid cells and shows an inverse correlation with the Ly6C marker and the C-C chemokine receptor 2 (CCR2) in the blood. This may indicate that CX3CR1 reduces the motility of Ly6C(high) monocytes in the bone marrow and thereby controls their release into the bloodstream.…”