Plasma Biomarkers Panel for Early Differential Diagnosis of Alzheimer’s Disease and Frontotemporal Dementia: Role of Soluble Fractalkine in Both Diseases and Against Inflammation in Cortical Neurons In Vitro

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Abstract
Frontotemporal lobar degeneration (FTD) is a proteinopathy that induces neuroinflammation and neurodegeneration; Alzheimer´s disease (AD) is characterized by Abeta-42 deposits, microglia overactivation, astroglial alterations and p-Tau accumulation. Identification of neuroinflammatory mediators as predictors of cognitive cognition have gained attention. We compared several biomarkers in plasma as predictors of cognitive impairment between AD and FTD patients (Nfl, p-Tau217, TDP-43 and CX3CR1 and soluble fractalkine levels) by ELISA (pg/ml) and age-matched controls (without cognitive impairment) or HIV-1 seropositive patients. To our knowledge, this is the first study showing that increased plasma CX3CR1 and soluble fractalkine predict cognitive impairment specifically in FTD. In addition, high plasma p-Tau 271 levels correlate with sFK levels and their mini mental scores in FTD. Thus, fractalkine and TDP-43 are exclusive biomarkers of cognitive impairment in FTD. However, Nfl, GFAP and p-Tau271 levels did not differ between AD or FTD patients. Anatomically, we observed hippocampal involution as well as Tau deposits in human FTD postmortem brains. On the other hand, neuroinflammation contributes to dementia; and chemokines as HIV-1 co-receptors facilitate spread of HIV-1 infection inducing apoptosis in the brain. On the other hand, chemokines promote neuronal survival and regulate neuron-glia interactions. Fractalkine is a delta chemokine (also termed CX3CL1), that binds to its CX3CR1 chemokine receptor, that as a membrane-isoform can be released as a soluble form by damaged neurons. We confirmed that fractalkine prevents LPS (an inflammation inductor)-induced apoptosis by decreasing caspase-3 activation in cortical neurons at 7 DIV LPS exposure. Thus, fractalkine may play a dual role: it is associated with cognitive impairment in both FTD and AD, yet it also exerts neuroprotective effects by reducing LPS-induced neuronal apoptosis at 7 DIV.

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