Inflammatory Chemokines Expression Variations and Their Receptors in APP/PS1 Mice

Abstract

Background:

In Alzheimer’s disease (AD), an increase in inflammation is distinctive. Amyloid precursor protein plus presenilin-1 (APP/PS1 mice) is a model for this illness. Chemokines secreted by central nervous system (CNS) cells could play multiple important roles in AD. Data looking for the chemokines involved in inflammatory mechanisms are lacking. To understand the changes that occur in the inflammation process in AD, it is necessary to improve strategies to act on specific inflammatory targets.

Objective:

Chemokines and their receptors involved in phagocytosis, demyelination, chemotaxis, and coagulation were the objective of our study.

Methods:

Female APPswe/PS1 double-transgenic mice (B6C3-Tg) were used and cortex brain from 20–22-month-old mice obtained and used to quantify chemokines and chemokine receptors expression using RT-PCR technique.

Results:

Significant inflammatory changes were detected in APP/PS1 compared to wild type mice. CCR1, CCR3, CCR4, and CCR9 were elevated, and CCR2 were decreased compared with wild type mice. Their ligands CCL7, CCL11, CCL17, CCL22, CCL25, and CXCL4 showed an increase expression; however, changes were not observed in CCL2 in APP/PS1 compared to wild type mice.

Conclusion:

This change in expression could explain the differences between AD patients and elderly people without this illness. This would provide a new strategy for the treatment of AD, with the possibility to act in specific inflammatory targets.

Keywords

Alzheimer’s disease APP/PS1 chemokine receptors chemokines inflammation

INTRODUCTION

Alzheimer’s disease (AD) is the major cause of dementia in older people. Progressive degeneration of cognitive functions and memory occurs with a gradual brain destruction. Major neuropathological hallmarks of AD are amyloid plaques, intracellular neurofibrillary tangles, activation of glia, and neural and synapses destruction [1 –4]. AD also presents as a chronic inflammatory disorder, detected both in the sick and in animal models [1 , 6], and the cytokines and chemokines produced play an important role in the development of the disease. In patients with AD, activation of microglia, astrocytes, and complement system led to a chronic immune response with neuron cell death [7]. On the other hand, it is known that neutrophils migrate to the amyloid plaques in some AD mouse model [8]. Inflammatory constituents include brain cells, the complement system, neuronal-type nicotinic acetylcholine receptors (AChRs), peroxisomal proliferators-activated receptors (PPARs), pentraxin acute-phase proteins, cytokines, and chemokines [9 –11]. Chemokines, first described as factors regulating migration of peripheral immune cells [12], have been involved in inflammatory actions, contributing to neurodegeneration and apoptotic cascades, mainly in AD [10, 13]. In fact, CCL4 expression has been found elevated in AD [14] and the chemokine CXCL10 and its receptor, CXCR3, have been found in high concentrations in both AD and APP/PS1 animal model [15]. In this transgenic model, CCL3 and CCL4 are overexpressed indicating an increase in astrogliosis and number of astrocytes compared with wild type mice [10 , 16–18]. But the involvement of many chemokines remains unknown, such as the chemokines investigated in our paper. The goal of this manuscript was to determine expression changes of chemokines and their receptors that are involved in inflammation and in neurodegeneration. Changes in expression of CCL2, CCL7, and CCL12 chemokines and their receptor CCR2, all involved in chemotaxis, were determined. Furthermore, we analyzed CCL17, and CCL22 and their receptor CCR4 because they regulate the proliferation, survival, and differentiation of hematopoietic cells, and have been detected in the CNS involved in cognitive impairment. On the other hand, CXCL4, involved in coagulation and its CCR1 receptor, a specific marker of AD [19 –21], were determined.

Moreover, CCL11, which selectively recruits eosinophils and is implicated in allergic responses, in junction with its receptor CCR3, were analyzed because the involvement in age and cognitive impairment detected in humans [14, 22] and in AD animal model [16 , 24]. Furthermore, CCL25 (CCR9 is it receptor) is mostly expressed in thymus and is involved in inflammation producing upregulation of cytokines conducting to cell death and has been published as a predictor of cognitive decline in mild cognition impairment (MCI) patients [23, 24] and in animal models [16]. All these chemokines are possibly implicated in brain inflammation and damage in APP/PS1 mice. These results may help to understand the inflammatory changes that occur in AD. These chemokines could constitute a possible therapeutic target in the treatment of AD [14 , 25–27].

MATERIALS AND METHODS

Animals

APPswe/PS1 double-transgenic mice (B6C3-Tg) and wild type littermates (WT) were used. APP/PS1 mice express a chimeric mouse/human APP 695 cDNA containing the Swedish (KM670/671 NL) mutation co-integrated with the human presenilin 1 (PS1) gene harboring the DE9 mutation. Two groups were assayed, APP/PS1 (five animals) and WT (five animals), and both were fed ad libitum on standard diet (Letica, Barcelona, Spain). Mice were kept on a 12 h light/12 h dark cycle with the room temperature maintained at 22°C. Pups aged 21–28 days old were removed from their parental cages and genotyped. All animal procedures were carried out in accordance with the European legislation on the use days and care of laboratory animals (CEE 86/609). Experimental research on mice was performed with the approval of the ethics committee on animal research of the University of Valencia (Spain). All mice used in the study were females. Brain was isolated from 20–22-month-old WT and APP/PS1 mice. Cortex was used in the experiments.

Real-time polymerase chain reaction analyses (RT-PCR)

Cortical brain samples were collected from each mouse into an RNAlater solution (Ambion, Austin, TX, USA), an RNA stabilization reagent, following the manufacturer’s instructions. Total RNA was extracted with Tripura isolation reagent (Roche Molecular Biochemical, Basel, Switzerland) and concentration and integrity were assessed in RNA 6000 Nano Labchips using Agilent 2100 Bio-analyzer (Agilent Technologies, Foster City, CA, USA). Ready-to-use primers and probes from the assay-on-demand service of Thermo Fisher Scientific were used for the quantification of selected target gene: CCL2 (Mm00441242_m1), CCL7 (Mm004431p_m1), CCL12 (Mm01617100_m1), CCR2 (Mm99999051_gH), CCL17 (Mm01244826_g1), CCL22 (Mm00436439_m1), CCR4 (Mm01963217_u1), CXCL4 (Mm00160719_cn), CCR1 (Mm00577746_cn), CCL11 (Mm00441238_m1), CCR3 (Mm00515543_s1), CCL25 (Mm00248750_cn), CCR9 (Mm00272668_cn), and endogenous reference gene β-actin (Mm00607939_s1) from Applied Biosistem. RNA samples were reverse transcribed using random hexamers and MultiScribe reverse transcriptase (Applied Biosystems). After complementary DNA synthesis, real-time polymerase chain reaction (RT-PCR) was carried out using the ABI Prism 7900HT Sequence Detection System (Applied Biosystems). The thermal profile consisted of 10 min of reverse transcription at 50°C, 10 min of hot-start enzyme activation at 95°C, followed by 45 cycles of PCR at 95°C for 10 s (denaturation), 58°C for 20 s (annealing), and 72°C for 30 s (elongation). Samples were run in triplicate, and expression changes were generated by calculating 2^–ΔΔCt.

Data analysis and statistics

All values are expressed as means±SD. The differences between transgenic (APP/PS1) and WT mice were determined with unpaired Student’s t-test. All statistical analyses were performed using the Graph-Pad Prism software (GraphPad Software Inc., San Diego, CA, USA). Statistical significance was accepted at p values < 0.05.

RESULTS

Expression of CCL2, CCL7, and CCL12 chemokines

Changes in these chemokines were tested by measuring RNA expression. In Fig. 1A, any different expression in CCL2 chemokine in APP/PS1 compared to WT mice were detected. On the other hand, significantly increased expression of CCL7 (mean±SD; 100.0%±9.2%versus 400.0%±98.7%; p < 0.05) and CCL12 (mean±SD; 100.0%±8.5%versus 250.5%±40.2%; p < 0.05) were noted in APP/PS1 cortex compared to WT mice (Fig. 1B, C).

Fig. 1

mRNA expression of A) CCL2, B) CCL7, and C) CCL12 in cortex of transgenic (TG) and wild type (WT) mice. Data are expressed as a percentage of control and are the mean±SD of four independent experiments. ^* p < 0.05 versus WT.

Expression of CCR2 receptor

CCR2 (C-C Motif Chemokine Receptor 2) is a protein coding gene associated with different diseases and can bind to CCL2, CCL7, and CCL12 chemokines. In Fig. 2, we can observe a 50%decrease in CCR2 mRNA expression in transgenic compared to WT mice (mean±SD;100.0%±11.2%versus 51.2%±4.8%; p < 0.05). Also, a reduction in CCR2 expression (mean±SD; 0.26±0.8 versus 0.1±0.05 relative densitometric units; p < 0.05) was noted, demonstrating a downregulation of the receptor when its chemokines CCL7 and CCL12 are increased (Fig. 2A, B).

Fig. 2

mRNA expression of CCR2 in cortex of transgenic (TG) and wild type (WT) mice. Data are expressed as a percentage of control and are the mean±SD of four independent experiments. ^* p < 0.05 versus WT.

Expression of CCL17 and CCL22 chemokines and its receptor CCR4

CCL17 and CCL22 regulate the proliferation, survival, and differentiation of hematopoietic cells and have been detected in the CNS, but their physiological role in neural cells is poorly understood in AD. We showed here an increase in CCL17 (mean±SD; 100.0%±10.5%versus 400.1%±30.2%; p < 0.05) and CCL22 (mean±SD; 100.0%±9.5%versus 150%±12.3%; p < 0.05) expressions in APP/PS1 compared to WT mice (Fig. 3A, B). CCR4 can bind to CCL17 and CCL22 chemokines. An increase in CCR4 expression was detected in APP/PS1 compared to WT mice, assessed by RT-PCR technique (mean±SD; 100.0%±8.5%versus 230.1%±25.2%; p < 0.05). Correlation between CCR4 and their chemokines (CCL17 and CCL22) exists (Fig. 3C).

Fig. 3

mRNA expression of A) CCL17, B) CCL22, and C) CCR4 in cortex of transgenic (TG) and wild type (WT) mice. Data are mean±SD of four independent experiments. ^* p < 0.05 versus WT.

Expression of CXCL4 and its receptor CCR1

CCR1 and its receptor CXCL4 are involved in coagulation. Figure 4 shows a significant increase of CXCL4 (mean±SD; 100.0%±24.1%versus 220.1%±15.3%; p < 0.05) in transgenic compared to WT mice (Fig. 4A). Moreover, its receptor, CCR1, showed higher expression in transgenic compared to WT mice (mean±SD; 100.0%±10.5%versus 150.2%±20.2%; p < 0.05) (Fig. 4B).

Fig. 4

mRNA expression of A) CXCL4 and B) CCR1 in cortex of transgenic (TG) and wild type (WT) mice. Data are mean±SD of four independent experiments. ^* p < 0.05 versus WT.

Expression of CCL11 and its receptor CCR3

mRNA expression of CCL11 chemokine and its receptor CCR3 were determined. This chemokine selectively recruits eosinophils and is implicated in allergic responses. CCL11 expression was higher in APP/PS1 compared to WT mice (50%±5) (Fig. 5A). On the other hand, CCR3 expression was higher in APP/PS1 compared to WT mice (100.0%±50%versus 250.3%±55%) (Fig. 5B).

Fig. 5

mRNA expression of A) CCL11 and B) CCR3 in cortex of transgenic (TG) and wild type (WT) mice. Data are the mean±SD of four independent experiments. ^* p < 0.05 versus WT.

Expression of CCL25 and its receptor CCR9

mRNA expression of CCL25 chemokine and its receptor CCR9 were determined. CCL25 expression was higher in transgenic compared to WT mice (mean±SD; 100.0%±12.2%versus 150%±30%; p < 0.05) (Fig. 6A). Moreover, its receptor, CCR9, showed lower expression in transgenic compared to WT mice (mean±SD; 100.0%±10.0%versus 250.2%±35.2%; p < 0.05).

Fig. 6

mRNA expression of A) CCL25 and B) CCR9 in cortex of transgenic (TG) and wild type (WT) mice. Data are mean±SD of four independent experiments. ^* p < 0.05 versus WT.

DISCUSSION

These results show that induction of inflammation, as well as chemotaxis, phagocytosis, and demyelination involved in AD, could be due to changes in chemokines and chemokine receptors. The levels of chemokines and their receptors changed in APP/PS1 compared to WT mice, happening in CCR2, CCR1, CCR4, CCR3, and CCR9 and in their ligands, CCL7, CCL12, CCL17, CCL22, CXCL4, CCL11, and CCL25. Chemokines secreted by CNS cells could play multiple roles in AD. We previously demonstrated that Aβ peptide induces inflammation and oxidative stress in neurons and astrocytes in primary culture [5 , 29]. In the present and previous studies, we have used the APP/PS1 mice model to assay changes in inflammatory mediators [10]. Previous results obtained in our laboratory demonstrated that changes in chemokines and chemokine receptors, such as CCR8 and CCR5 receptors and their chemokines (CCL1, CCL3, CCL4, and CCL5), are involved in inflammation process in APP/PS1 mice [10]. This manuscript shows that changes in chemokines and their receptors are important in the inflammatory process in APP/PS1 mice.

Ligands and receptors of chemokines are in general expressed both in adult and developed CNS [30, 31]. New mechanisms and physiological functions have been evidenced for chemokines in the CNS, including endocrine regulation, neuromodulation, and different effects like those evoked by neurotransmitters [31 –33]. CNS cells express specifically different receptors: neurons express CXCR2, CXCR3, and CXCR4; astrocytes express CXCR2, CXCR4, CCR1, CCR2, CCR3, CCR5, CCR10, CCR11, and CX3CR; and microglia express CCR2, CCR5, and CX3CR1 [28, 34]. Several chemokines are constitutively expressed in normal conditions, including CCL2 and CCL19 [30, 35]. Other chemokines are upregulated after inflammation (CCL7 and CCL12). Pro-inflammatory chemokines drive cells by chemotaxis to the inflamed CNS, such as CCL2, CCL7, and CCL12 [36]. Transgenic overexpression of CCL2 in the brain produces increase in microglia accumulation and amyloid plaque deposition in APP mutant mice [37]. Under our conditions we did not detect significant changes in this chemokine. In a primary Ra2 microglial cell line, Aβ_1–42 induced the expression of CCL3, CCL4, and CCL7 chemokines [10, 38]. It should be noted that dendritic cell-derived factor 1 (Dcf1) plays a role in neuronal AD and, in addition, Dcf1^–/– mice presents increment on microglial function by growing microglial activation markers expression, such as certain inflammatory chemokines [39]. Moreover, CCL7 and CCL12 exert potent pro-inflammatory actions through leukocyte chemotaxis in the inflamed CNS after ischemia in rats [40]. Our results demonstrated a higher expression of CCL7 and CCL12 in APP/PS1 compared with WT mice.

In humans, using RT-PCR, an increase of CCL2 mRNA levels in AD temporal cortex compared to controls was detected. CCL12 chemokine is found under normal conditions in lymph nodes and thymus and can be highly induced in macrophages [30]. Coordination of cell movement during allergic reactions and the immune response to pathogens is believed to be done by CCL12 [41]. The APP/PS1 mouse model develops Aβ plaques and presents cognitive impairments from 7 months of age [10, 42]. Furthermore, it seems likely that activation of glial cells, together with presence of chemokines, could be before Aβ appears in plaques. In AD rat models, animals under stress show upregulation of CCL12 that is implicated in neuroinflammation [43]. CCR2 (C-C Motif Chemokine Receptor 2) is a protein that can bind CCL2, CCL7, and CCL12 chemokines [35 , 45]. The receptor is expressed in astrocytes, neurons, and microglia under basal or inflammatory conditions [46, 47]. In APP/PS1 mice, increased expression of CCL2 and CCR2 produced β-amyloidosis with higher degree of oligomer formation [48]. A decrement in Aβ phagocytosis and amyloid elimination occurs after CCL2 and CCR2 deficiency, suggesting that this chemokine and its receptor may be important in maintaining the neuronal homeostasis [49]. Furthermore, monocytes positive to CCR2 play a significant role protecting neuronal cells, because their damage may be associated with neuronal degeneration [50]. Here we detected a decrease of CCR2 expression in APP/PS1 mice compared to WT, probably because of a decrease in the migration and recruitment of inflammatory monocytes to the amyloid site occurs. Similarly, a decrease in CCR2 expression has been related with aggravation of amyloid deposition and cognitive impairment in a transgenic mouse model of AD [51]. Furthermore, studies with CCR2^–/– mice showed a reduction in number and survival of microglial cells, with an increase in Aβ [52]. Other authors have indicated a decrease in survival and an increase in Aβ load in APP or APP/PS1 transgenic mice with a reduction in microglia cell number in the brain with also a decrement in CCR2 expression [53]. Additionally, CCR2 deficiency has been implicated with a rapid development of AD-like pathologies compared to control mice [53, 54].

CCR4 bind CCL17 and CCL22 chemokines [55]. This receptor is expressed by astrocytes and neurons [56]. Our results shown an increase in CCL17, CCL22, and CCR4 expression in APP/PS1 mice compared with WT. In patients with AD, the number of cells expressing CCR4 are increased, and this fact may constitute a new target for immune therapies in AD [57]. High levels of CCL17 and CCL22 have been detected in multiple sclerosis and moreover, the axis CCL17-CCL22-CCR4 has been proposed as a possible therapeutic target in autoimmune diseases [58]. Furthermore, CCL17, CCL22, and CCR4 are implicated in a model of autoimmune encephalomyelitis [59]. Also, CCL17 deficiency is associated with beneficial CNS immune responses. In CCL17-deficient APP/PS1 mice, there is a reduction in the Aβ peptide due to an increase in its elimination and a lesser loss of neurons, as well as less cognitive deterioration [60]. Elevated level of CCL22 have been associated with cognitive impairment suggesting a peripheral inflammatory response to neurodegeneration [61], and CCL22 decrease has been associated with reduction of inflammation and demyelination [62].

In this study we detected a significant increase in CCR1 and its CXCL4 chemokine in the mouse model used. CXCL4 is an agonist of CCR1 and are involved in human monocyte migration, inducing monocyte chemotaxis and also playing an inflammatory role [63]. Its physiologic role appears to be neutralization of heparin-like molecules on the endothelium of the blood vessels, inhibiting local antithrombin activity and promoting coagulation [64]. CCR1 is a specific marker of AD but is not related to Aβ_1–42 deposition [20]. CXCL4 enhances CCL5 effects [65] amplifying endothelium monocyte arrest [66] and CCL5 also binds to the CCR1 receptor [67]. In our previous study, we demonstrated no changes in CCL5 expression in APP/PS1 mice [10], suggesting that the increase in the expression of CCR1 detected in the present study may be linked to that of CXCL4.

In our results, an increase in CCL11 chemokine and CCR3 expression were noted. CCL11 has a role in neuroinflammation and neurodegeneration [68]. Its CCR3 receptor is expressed in different brain cells, like astrocytes and neurons, and binds CCL11 chemokine so efficiently [69]. An association has been shown between age and increased CCL11 levels in plasma, in both mice and humans [22] and between AD and increased CCL11 plasma levels [33, 34]. CCL11 and its receptor CCR3 are involved in aging, elevated tau phosphorylation, Aβ deposition, astrogliosis, and memory impairment [16, 70]. Additionally, young mice exposed to CCL11 or blood plasma of older mice present decrease in neurogenesis and cognitive performance on behavioral tasks [70]. Moreover, this chemokine has been found at high concentrations in schizophrenia patients and in cannabis users [71].

Our results indicated an increase in CCR9 and CCL25 expression in APP/PS1 mice. CCR9 is expressed in microglia from cerebral cortex, hippocampus, and cerebellum [72, 73]. CCL25 is a ligand of CCR9 expressed in epithelial and brain cells [74] and can predict cognitive decline in MCI in patients [75]. CCL25/CCR9 signal mediates Th17 infiltration induced by Toll-like receptor 4 in experimental autoimmune encephalomyelitis [76], and CCL25 level is increased in ulcerative colitis patients, with implication of CCR9/CCL25 as an etiological agent [77]. Moreover, CCR9 and its ligand CCL25 mediate gamma delta T cells migration to the small intestine [77]. In this sense, the clinical use of CCR9 antagonists has been proposed, and in fact, pharmacological antagonism of CCR9 reduce inflammatory cytokine levels and severity in Crohn’s disease [78]. CCL25 and CCR9 receptor weaken beta-cell functionality and inhibit insulin release, inducing the cytokine apoptosis mechanism. In obesity, upregulation of CCR9 facilitates immune cell accumulation and metabolic dysfunction [79].

CONCLUSIONS

These results show that induction of inflammation, as well as chemotaxis, phagocytosis, and demyelination involved in AD, could be due to changes in chemokines and chemokine receptors. Chemokines secreted by CNS cells could play multiple roles in AD. Level of chemokines and their receptors changed in APP/PS1 compared to WT mice, occurring in CCR2, CCR1, CCR4, CCR3, and CCR9 and in their ligands, CCL7, CCL12, CCL17, CCL22, CXCL4, CCL11, and CCL25. This could provide a new strategy for the treatment of AD, with the possibility to act in specific inflammatory targets.

Footnotes

ACKNOWLEDGMENTS

The APP/PS1 mice were provided by Dr. Juan Gambini, School of Medicine. All other material was obtained from each researcher.

Authors’ disclosures available online ().

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