High Cerebrospinal Fluid CX3CL1 Levels in Alzheimer’s Disease Patients but Not in Non-Alzheimer’s Disease Dementia

Abstract

Alzheimer’s disease (AD) is the most common form of cognitive decline worldwide, occurring in about 10% of people older than 65 years. The well-known hallmarks of AD are extracellular aggregates of amyloid β (Aβ) and intracellular neurofibrillary tangles (NFTs) of tau protein. The evidence that Aβ overproduction leads to AD has paved the way for the AD pathogenesis amyloid cascade hypothesis, which proposes that the neuronal damage is sustained by Aβ overproduction. Consistently, AD cerebrospinal fluid (CSF) biomarkers used in clinical practice, including Aβ 1–42, Aβ 1–40, Aβ 42/40 ratio, and pTau, are related to the amyloid hypothesis. Recently, it was suggested that the Aβ deposition cascade cannot fully disclose AD pathogenesis, with other putative players being involved in the pathophysiology of the disease. Among all, one of the most studied factors is inflammation in the brain. Hence, biomarkers of inflammation and microglia activation have also been proposed to identify AD. Among them, CX3 chemokine ligand 1 (CX3CL1) has taken center stage. This transmembrane protein, also known as fractalkine (FKN), is normally expressed in neurons, featuring an N-terminal chemokine domain and an extended mucin-like stalk, following a short intra-cytoplasmatic domain. The molecule exists in both membrane-bound and soluble forms. It is accepted that the soluble and membrane-bound forms of FKN evoke differential signaling within the CNS. Given the link between CX3XL1 and microglial activation, it has been suggested that CX3CL1 signaling disruption could play a part in the pathogenesis of AD. Furthermore, a role for chemokine as a biomarker has been proposed. However, the findings collected are controversial. The current study aimed to describe the cerebrospinal fluid (CSF) levels of CX3XL1 and classical biomarkers in AD patients.

Effects of Cerebrospinal Fluids from Alzheimer and Non-Alzheimer Patients on Neurons–Astrocytes–Microglia Co-Culture

“…The CSF samples used were selected from those analyzed in a previous study we conducted [ 17 ]. As reported in Table 1 , the three different groups, Aβ+Tau, Aβ-Tau, and non-AD (four patients per group), were selected to have a very low variability compared to the average value of the different markers used for their characterization biochemistry of being AD or non-AD subjects.…”

“…The results obtained highlighted the presence of CX3CL1 for a quantity greater than 40% in subjects with AD compared to non-AD subjects. This suggests that CX3CL1 could be considered a possible new marker for Alzheimer’s in the disease [ 17 ].…”

“…In this work, we went to evaluate how the cerebrospinal fluid, rich in the sCX3CL1 form, characterized based on canonical markers of Alzheimer’s disease in a previous work [ 17 ], from Alzheimer’s and non-Alzheimer’s subjects (other neurodegenerative pathologies) influenced the expression of specific markers on an “in vitro” co-culture of neurons–astrocytes–microglia (NAM).…”

Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives

“…Many studies have been performed on the cerebrospinal fluid (CSF) of AD patients, reporting CX3CL1 levels to be elevated. However, contrarily, some authors have documented opposite findings [69,71].…”

Recovery of Bioactive Compounds from Marine Organisms: Focus on the Future Perspectives for Pharmacological, Biomedical and Regenerative Medicine Applications of Marine Collagen

“…In addition to their antioxidant, antithrombotic, anticoagulant, anti-inflammatory, antiproliferative, antihypertensive, antidiabetic, and cardioprotective properties, marine-sourced biocompounds have been investigated for their neuroprotective potential [ 106 ]. Neurodegeneration is a complex, progressive multifactorial process that leads to the loss and death of neuronal structures in the nervous system; it is associated with the accumulation of insoluble deposits of protein and peptide aggregates, generally containing misfolded proteins, in different areas of the brain and spinal cord [ 107 ]. As oxidative stress has been considered to play an essential role in the onset and progression of neurodegeneration, there has been a significant scientific focus on the development of antioxidant compounds for neuroprotection [ 108 ].…”