This needs to be further clarified. The expression of CX3CL1 is decreased in cerebral cortex and hippocampus ZM 323881 hydrochloride of APP transgenic mice while it is increased in tau-injured neurons [36, 37]. p-tau accumulation in AD [14]. All the above show that CX3CL1 has a major role in the progression of AD. In this review, we summarize the multiple functions of CX3CL1 CDC42 in neuroinflammation, neurotoxicity, and synaptic plasticity in AD pathogenesis. 2. CX3CL1/CX3CR1 and Microglia CX3CL1 is usually a large cytokine protein of 373 amino acids with an extended mucin-like stalk and a chemokine domain name on top. It is the only member of CX3C family which belongs to the large family of small secreted chemotactic cytokines. CX3CL1 is usually expressed with particularly high levels in hippocampal and cortical neurons constitutively but none on microglia [15]. It exists in both secreted and membrane-bound form and its membrane-tethered mucin stalk acts as a cell adhesion molecule adhering to microglia during an inflammatory reaction [16]. The membrane-bound form can be cleaved in the condition of cathepsin S, ADAM-10, and ADAM-17; then the soluble one can serve as a signaling molecule mediating neural/microglial interactions via its sole receptor CX3CR1 that is mainly expressed on microglia and partly on astrocyte as well as on neurons in the CNS [17C19]. These suggest that CX3CL1/CX3CR1 is an important bridge to connect neuron and microglia. Microglia, ZM 323881 hydrochloride resident mononuclear phagocytes in the CNS, intimately involved in the development of the nervous system, are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions [20, ZM 323881 hydrochloride 21]. It has been exhibited that Aburdened neurons inducing microglial activation may be an early phenomenon in the procession of AD [22]. However, microglia activation in AD is usually suggested to be heterogeneous: beneficial or harmful [23]. This may be associated with microglia activation phenotype which includes M1 (iNOS+ microglia) and M2 (Arg+ microglia); iNOS+ microglia induce production of neuroinflammation factors while Arg+ microglia have enhanced phagocytic activity. In accordance with this, greater numbers of Arg+ microglia made up of Awere found when compared to iNOS+ microglia in the inflamed hemisphere [24]. Moreover, amounts of evidence indicate that microglia phenotype changes from M2 to M1 in the progression of AD [25]. Neuronal soluble CX3CL1 is likely to alter the microglial state to a more neuroprotective one by acting on CX3CR1 in ZM 323881 hydrochloride microglia [26]. This also has been confirmed that disruption of CX3CL1-CX3CR1 leads to dysregulate microglial responses and neuronal damage [12, 18]. Besides, hAPP-CX3CR1?/? mice as well as hTau-CX3CR1?/? mice showed increased expression of inflammatory factors, enhanced tau phosphorylation, and exacerbated plaque-independent neuronal dysfunction and cognitive deficits [27, 28], while researches also exhibited that both APP-PS1/CX3CR1?/? and CRND8/CX3CR1?/? mice showed reduction in Adeposition with increased number of microglia [29, 30]. Moreover, the suppression of CX3CL1-CX3CR1 alleviated Adeposition. Overexpression of soluble CX3CL1 by adeno-associated viral (AAV) vectors plays an active role in reducing ZM 323881 hydrochloride tau pathology and neuron loss, while it has no effect on Adeposition indicating that additional CX3CL1 signaling has no additive effect on Adeposition [26, 33]. Surprisingly, neither enhanced tau phosphorylation nor reduced Adeposition in CX3CL1-deficient APP-PS1 animals was altered by soluble CX3CL1 isoform, which was introduced by bacterial artificial chromosome (BAC) transgene encoding truncated CX3CL1 [34]. Thus making the function of soluble CX3CL1 is usually full of doubt. A possible explanation is usually that AAV vectors might make soluble CX3CL1 build the required local gradient and it should suffice, while the only soluble CX3CL1 can be diluted rapidly [35]. This needs to be further clarified. The expression of CX3CL1 is usually decreased in cerebral cortex and hippocampus of APP transgenic mice while it is usually increased in tau-injured neurons [36, 37]. Moreover, the level of plasma soluble CX3CL1 is usually significantly greater in the patients with moderate to moderate AD than.