Age-dependent changes on fractalkine forms and their contribution to neurodegenerative diseases

The chemokine fractalkine (FKN, CX₃CL1), a member of the CX₃C subfamily, contributes to neuron–glia interaction and the regulation of microglial cell activation. Fractalkine is expressed by neurons as a membrane-bound protein (mCX₃CL1) that can be cleaved by extracellular proteases generating several sCX₃CL1 forms. sCX₃CL1, containing the chemokine domain, and mCX₃CL1 have high affinity by their unique receptor (CX₃CR1) which, physiologically, is only found in microglia, a resident immune cell of the CNS. The activation of CX₃CR1contributes to survival and maturation of the neural network during development, glutamatergic synaptic transmission, synaptic plasticity, cognition, neuropathic pain, and inflammatory regulation in the adult brain. Indeed, the various CX₃CL1 forms appear in some cases to serve an anti-inflammatory role of microglia, whereas in others, they have a pro-inflammatory role, aggravating neurological disorders. In the last decade, evidence points to the fact that sCX₃CL1 and mCX₃CL1 exhibit selective and differential effects on their targets. Thus, the balance in their level and activity will impact on neuron–microglia interaction. This review is focused on the description of factors determining the emergence of distinct fractalkine forms, their age-dependent changes, and how they contribute to neuroinflammation and neurodegenerative diseases. Changes in the balance among various fractalkine forms may be one of the mechanisms on which converge aging, chronic CNS inflammation, and neurodegeneration.