The endogenous α7 nicotinic acetylcholine receptor antagonist kynurenic acid modulates amyloid-β-induced inflammation in BV-2 microglial cells
Introduction
Alzheimer disease (AD) is the most common neurodegenerative disease affecting more than 30 million people in the world. The main pathological hallmarks are the extracellular formation of amyloid-β (Aβ) plaques and the intracellular formation of neurofibrillary tangles, composed of hyperphosphorylated tau-protein [5]. Post-mortem analysis of AD brains also shows the involvement of activated microglial cells [23]. It has already been shown that soluble oligomeric forms of Aβ are able to induce microglial activation [34] and some therapeutic approaches, such as non-steroidal anti-inflammatory drugs, are able to prevent microglial actication in vitro. Cholinergic neurons in the nucleus basalis Meynert seem to be extremely vulnerable to Aβ toxicity and cognitive dysfunctions are especially connected to the loss of these cholinergic neurons [3]. There is evidence that Aβ oligomers interact with the α7 nicotinic acetylcholine receptor (α7nAChR) on neuronal cells in vitro [36]. The interaction of Aβ and the α7nAchR results in elevated intracellular calcium levels in neurons [26] pointing to the role of Aβ as an α7nAChR agonist. Even subtle changes in intracellular calcium levels induce a plethora of signalling events resulting in augmentation of Aβ formation as well as hyperphosphorylation of tau protein [19]. To date the role of the interaction of Aβ and α7nAChR on microglial cells is not clear. Expression of the α7nAChR on primary mouse microglia and BV-2 microglial cells has been reported as well as the involvement of this receptor in the modulation of microglial activation [22], [29]. Considerable empirical evidence suggests a neuroprotective role of nicotine in an endogenous anti-inflammatory pathway, in which activation of monocytes is regulated by α7nAChR [35]. However, it is not clear whether this effect is due to activation or inhibition of the α7nAChR. It is assumed that the anti-inflammatory effect of nicotine is not due to its agonistic activity on the α7nAchR, because very high concentrations of nicotine that even desensitize the receptor are needed to obtain an anti-inflammatory effect [6]. Astrocytes are believed, among others, to control microglial activation and are able to synthesize ACh as well as the endogenous potent α7nAChR antagonist kynurenic acid (KYNA); thus, microglial activation might be regulated via cholinergic signalling [17], [37]. KYNA and quinolinic acid (QA) are by-products of tryptophan degradation. QA exerts toxic effects on neurons [33] and KYNA is able to reduce this toxic effects, most likely due to its antagonistic activity on α7nAchR [12]. In states of inflammation enhanced concentration of indoleamin 2,3-dioxygenase can be detected leading to an increase in QA [27]. In addition, it has been shown that Aβ-activated human microglial cells synthesize larger amounts of quinolinic acid [11], pointing to a possible regulatory role of KYNA in Aβ-induced neuroinflammation.
Interestingly in human serum and cerebrospinal fluid of AD patients lower concentrations of KYNA compared to healthy controls could be detected, whereas the level of KYNA is enhanced in the putamen and caudate nucleus of AD patients [2], [12], [13]. In conclusion it has to be stated that the role of KNYA in AD is unclear so far. Thus, it is of considerable interest to investigate the role of the endogenous α7nAchR antagonist KYNA on Aβ-induced microglial neuroinflammation.
Section snippets
Material and methods
All chemicals were obtained from Sigma-Aldrich, St. Louis, MO, USA, unless indicated otherwise.
Aβ and KYNA do not influence the quantity of α7nAchR in BV-2 cell lysates
To investigate the quantity of α7nAchR on BV-2 cells, BV-2 cell lysates were subjected to Western blotting and α7nAchR was detected with a monoclonal antibody (sc-5544). In addition, cells were treated with 5 μM Aβ oligomers and/or 1 μM, 10 μM and 100 μM KYNA for 24 h to investigate the influence of those on the α7nAchR expression, because an influence on α7nAchR expression on neuronal cells has been previously shown in AD brains [8]. However no difference in α7nAchR expression was observed in BV-2
Discussion
There is considerable evidence that microglial cells exert an influence on the development and progression of AD. Aβ is able to induce neuroinflammation [15] and also reduces the viability of neurons [1]. KYNA has been assigned a neuroprotective role in neurodegeneration as well as in ischemia [17], [38] and it has been shown that KYNA binds to the α7nAchR and promotes an antagonistic effect [17]. As a member of the cholinergic anti-inflammatory pathway the α7nAchR plays a pivotal role in the
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgements
We would like to thank Christine Forbach for excellent technical assistance.
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