Golgi Apparatus Polarity Indicates Depression-like Behaviours of Mice

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Golgi Apparatus Polarity Indicates Depression-like Behaviours of Mice Using in vivo Fluorescence Imaging Ping Li, Xiaomeng Guo, Xiaoyi Bai, Xin Wang, Qi Ding, Wen Zhang, Wei Zhang, and Bo Tang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b04703 • Publication Date (Web): 08 Feb 2019 Downloaded from http://pubs.acs.org on February 8, 2019

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Analytical Chemistry

Golgi Apparatus Polarity Indicates Depression-like Behaviours of Mice Using in vivo Fluorescence Imaging Ping Li‡, Xiaomeng Guo‡, Xiaoyi Bai, Xin Wang, Qi Ding, Wen Zhang, Wei Zhang and Bo Tang* College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Edu-cation, Shandong Normal University, Jinan 250014, P. R. China.. ABSTRACT: Depression is associated with decreased expression of brain-derived neurotrophic factor (BDNF) which assembled in Golgi apparatus. The changes might be closely related to variation in Golgi apparatus polarity. Thus, developing a nondestructive method to detect polarity in living cells and in vivo can facilitate accurate diagnosis and prognosis of depression. Herein, we created a new near infrared Golgi-targetable fluorescent probe (Golgi-P) in which the merocyanine and benzoyl difluoroboronate moieties sense polarity changes. Golgi-P exhibited a decrease in fluorescence intensity and redshift of maximum emission wavelength as the increase in polarity. Using Golgi-P, we discovered distinctly higher polarity in brains of mice with depression phenotype for the first time. Furthermore, our results disclosed that the elevation of polarity could due to the reduced synthesis of BDNF. Altogether, this study offers a new strategy for the accurate diagnosis of depression.

Depression is a devastating mental disease with high morbidity and mortality rates, which seriously endangers human health and brings severe social and economic problems.1,2 However, current diagnosis of depression is subjective and based on symptoms overlapping with many other psychological or physiological problems.3 Therefore, there is an urgent need to establish a golden standard for the accurate diagnosis of depression. Brain-derived neurotrophic factor (BDNF), assembled in the Golgi apparatus, plays a crucial role in regulating the nervous system functions.4 The neurotrophic hypothesis also suggests that depression is associated with the decreased expression and functional degeneration of BDNF. Additionally, the expression of BDNF was significantly upregulated during chronic antidepressant treatment.5 Golgi apparatus as the site of BDNF processing, its microenvironment including polarity could be causally related to the level of BDNF, and thereby the changes of Golgi apparatus polarity can effectively indicate occurrence and development of depression. Therefore, developing a nondestructive, in situ and instantaneous method to detect the polarity in the Golgi apparatus and brains of mice with depression phenotype is beneficial for accurate diagnosis of depression. Fluorescence imaging possessed high temporal-spatial resolution and nondestruction has become an emerging technology for disease diagnosis in recent years.6-8 Particularly, near infrared (NIR) fluorescence imaging has been widely used in deep tissue and in vivo imaging due to little photodamage and deep tissue penetration depth with low background fluorescence interference.9-14 An increasing number of NIR fluorescent probes for detecting various bioactive species have been developed over the past few

years.15-19 The advent of these probes has greatly facilitated the development of cell biology and diagnostic imaging. However, there has been no report on visualizing the polarity changes of the Golgi apparatus in living brains of mice with depression-like behaviors, especially using NIR fluorescence imaging. Scheme 1 The chemical structure of Golgi-P.

To solve this issue, we herein created a Golgi apparatustargetable NIR fluorescent probe termed Golgi-P (Scheme 1). In Golgi-P, the merocyanine and benzoyl difluoroboronate moieties serve as electron donating and accepting groups, causing the excited state intramolecular charge transfer (ICT). In polar media, the excited state energy can be dissipated due to the dipole–dipole interaction between the probe molecules and solvent, which is responsible for the polarity sensitivity. Therefore, the probe exhibits weak fluorescence and a longer emission wavelength in polar media, and in contrast, a stronger fluorescence and shorter emission wavelength in nonpolar media. 20-23 The large conjugated skeleton endows Golgi-P maximum NIR excitation and emission wavelengths.20 Lcysteine was introduced to realize the Golgi apparatustargeting.24,25 We proved that the maximum emission wavelength of Golgi-P showed distinct polarity dependence. Golgi-P could solely accumulate into the Golgi apparatus and indicate polarity changes. Furthermore, utilizing Golgi-

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P, we identified the polarity level and the BDNF content in the brains of the mice with depression-like behaviours.

EXPERIMENTAL SECTION Synthesis of Compounds. Compounds a, c and d were synthesized as references (Scheme 2).26,27 Scheme 2. The synthetic process of Golgi-P.

Synthesis of Compound b.24 First, 1.5 equivalents of EDC and HOBT and 3 equivalents of triethylamine were added to a flask containing compound a and L-cysteine dissolved with methylene chloride under nitrogen. The mixture was stirred overnight at room temperature. The crude product was purified by TLC using CH2Cl2:CH3OH (10:1) as the eluent to give compound b. Rf: 0.28. Yield: 41.6 %. HRMS (ESI) m/z calcd. for C17H23N2O3S+[M]: 335.1424, found 335.1420. Synthesis of Golgi-P.20 A mixture of compound c and compound d was placed into a flask containing acetic anhydride under nitrogen atmosphere, and after 1 equivalent of sodium acetate was added, the mixture was stirred at 65 °C. After 5 hours, compound b was put into the flask and stirred continuously for 1 hour. Afterward, the mixture was extracted with saturated NaHCO3 solution, H2O and dichloromethane. The organic layers were dried over Na2SO4 and evaporated under reduced pressure. The compound Golgi-P was obtained as a green solid by TLC using CH2Cl2:CH3OH (100:3) as the eluent. Rf 0.27. Yield: 2.5 %. HRMS (ESI) m/z calcd. for C35H36BClF2N2O5S[M-F+Na]+: 684.2010, found 684.2017. 1H NMR (400 MHz, MeOD) δ(ppm): 1.27 (s, 6H), 1.55 (s,1H), 2.03 (t, 2H), 2.17 (t, 2H), 2.39 (m, 2H), 2.48 (t, 2H), 2.70 (m, 2H), 3.94 (m, 1H), 3.96 (d, 1H), 4.00 (d, 1H), 4.12 (d, 1H), 5.28 (d, 1H), 6.84 (s, 1H), 6.88 (d, 1H), 6.94 (t, 1H), 7.26 (t, 1H), 7.34 (t, 1H), 7.45 (d, 1H), 7.53 (m, 1H), 7.75 (t, 1H), 7.84 (d, 1H), 7.99 (s, 1H). 13C NMR (100 MHz, d6-DMSO) δ(ppm): 14.43, 22.42, 22.57, 25.57, 27.02, 27.06, 27.39, 29.04, 31.74, 35.51, 45.71, 48.09, 84.18, 93.77, 108.54, 109.31, 112.09, 118.39, 120.10, 121.84, 122.74, 127.73, 127.82, 128.43, 128.87, 129.13, 130.10, 143.34, 143.62, 144.12, 147.76, 168.84, 173.20, 174.27, 174.80.

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(P = 7.2), the maximum was 810 nm. Meanwhile, when excited at 700 nm, the fluorescence spectra of Golgi-P at the same concentration (10 μM) showed clear polarity dependence and a shift of the maximum emission wavelength (Figure 1B). That is to say, the probe exhibited a low fluorescence intensity and fluorescence quantum yield in the high-polarity environment. On the contrary, it presented brighter fluorescence and higher fluorescence quantum yield in the low-polarity environment. The fluorescence intensity of Golgi-P at 780 nm in toluene was about 24 times higher than that in DMSO. The above experimental results prove that the fluorescence signal of the probe is polarity-dependent.

Figure 1. The normalized absorption (A) and fluorescence spectra (B) of Golgi-P (10 μM) in common solvents with different polarities. (λex=700 nm).

We then planned to accurately quantify the polarity in the various microenvironment using the probe’s fluorescence signal ratio at 825/800 nm. The different polarities were simulated with a dioxane-water system by changing their ratios. We investigated the fluorescence spectra of Golgi-P in these mixtures. Golgi-P exhibited highly sensitive to the microenvironment in different solvent proportions of this mixed system (Figure S1). As illustrated in Figure 2A, the intensity of Golgi-P enhanced gradually, and the maximum emission wavelength shifted as the decrease in polarity. A calibration curve with a correlation coefficient of 0.998 was obtained by plotting the fluorescence intensity ratio at the two wavelengths of 825 nm and 800 nm against the dielectric constant of the mixed system (Figure 2B). By detecting the ratio of F825/F800, Golgi-P can be used to accurately determine the polarity (dielectric constant) of the environment. These results show that Golgi-P as an extraordinary fluorescent probe processed high sensitivity to polarity can quantitatively indicate the polarity of environment.

RESULTS AND DISCUSSION. Optical Properties and Sensitivity towards Polarity. Firstly, we examined the UV absorbance and fluorescence spectra of the probe Golgi-P in detail at different polarities. The spectral data of Golgi-P in seven solvents are summarized in Table S1. As shown in Figure 1A, the maximum absorption wavelength of Golgi-P red-shifted to some extent with the increase of the polarity index (P) in six common solvents. For example, the maximum absorption wavelength in toluene (P = 2.4) was 735 nm, while in DMSO

Figure 2. (A) The fluorescence spectra of Golgi-P (10 μM) in dioxane-water mixtures (water from 0 to 70 %). (B) The fluorescence intensity ratio of 825 and 800 nm with the dielectric constant. (λex=700 nm).

Specificity of Golgi-P towards Polarity. Having determined the sensitivity of Golgi-P to polarity, we next investigated the specificity by measure its fluorescence response to some biologically relevant species (Figure 3).


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Analytical Chemistry Due to the larger P of water, the probe Golgi-P had almost no fluorescence in water. With the addition of various metal ions, amino acids, and reactive oxygen species to Golgi-P, there was almost no change in the fluorescence intensity. In contrast, the same concentration of Golgi-P showed very strong fluorescence in tetrahydrofuran with a smaller P. In addition, we testified that Golgi-P was unsensitive to pH and viscosity (Figure S2, S3). It also displayed good photostability (Figure S4). All these data demonstrate that Golgi-P possesses high selectivity to polarity, as well as superior photostability. These virtues allow it to monitor the changes of polarity in living cells and in vivo.

Figure 3. (A) Fluorescence response of Golgi-P (10 μM) to different kinds of metal ions (Ca2+, Sr2+, K+, Cu2+, Sn4+, Ni2+, Cu+, Na+, Ba2+, Mg2+, Fe3+, Mn2+, Al3+, and Zn2+). (B) Fluorescence response of Golgi-P (10 μM) to different kinds of reactive oxygen species (ROS) and amino acids (H2O2, HClO, O2•-, •OH, ONOO-, GSH, Cys, Asn, Gln, Thr, and Ser). (λex=700 nm).

a co-location coefficient of 0.93 (Figure 4F, 4G). This demonstrates that cysteine residues could effectively guide the probe to the Golgi apparatus. We also verified the localization ability of Golgi-P in HL-7702 cells (Figure S6). Given the large polarity of the extracellular environment, there is virtually no associated fluorescence. Therefore, we also performed cell staining experiments without washing (Figure S7). The results showed that Golgi-P still possessed an excellent signal-noise ratio, so it can be applied to nonwashing cell staining experiments, which can simplify the operation process. The above results demonstrate that Golgi-P exhibits superior biocompatibility and Golgi apparatus targetability. Imaging Polarity Change in Cells. Next, we intended to examine the local polarity in living cells with Golgi-P. Previous studies have shown that cancer cell mitochondria have a lower-polarity environment. We herein detected the polarity of the Golgi apparatus in normal and cancer cells. As shown in Figure 5 and S8, the fluorescence of Golgi-P in SMMC-7721 is higher than that of HL-7702 cells, indicated that the Golgi apparatus of the cancer cells presented a lower polarity. This result highlights the fact that Golgi-P can track the changes of polarity in Golgi apparatus at cellular level.

Cytotoxicity and Co-localization Ability. With these satisfactory properties, we next intended to explore Golgi-P imaging applications in living cells. Before the experiment, Golgi-P was proven to be low cytotoxic via MTT (3-[4, 5dimethylthiazol-2-yl]-2, 5 diphenyl tetrazolium bromide)assays (Figure S5).

Figure 5. Confocal fluorescence images of HL-7702 (A-C) and SMMC-7721 (D-F) cells stained with Golgi-P (20 μM). λex=633 nm, collected at 720 nm-800 nm. (G) Fluorescence intensity output of Golgi-P in A (pink) and D (blue).

Figure 4. The co-localization fluorescence images of Golgi-P in PC12 cells. (A) Golgi-P (20 μM) stain, λex=633 nm, collected at 720 nm-800 nm. (B) Golgi Tracker Red (500 nM) stain, λex=561 nm, collected at 580 nm-620 nm. (C) Merged image of A and B. (D) The bright-field image. (E) Merged image of A and B and D. (F-G) Co-location coefficient of Golgi-P and Golgi Tracker Red.

To verify that the probe could preferably accumulate into the Golgi apparatus, we performed a co-localization experiment using Golgi-P with a commercialized dye for the Golgi apparatus (Golgi Tracker Red) in living cells. PC12 cells were incubated with Golgi-P (20 μM) and Golgi Tracker Red for 30 min, after which the cells were washed 3 times with PBS to remove excess probe and dye. The fluorescence images of Golgi-P and Golgi Tracker Red were collected by confocal fluorescence microscopy. Figure 4C show that Golgi-P overlapped well with the Golgi apparatus dye, with

Figure 6. Confocal fluorescence images of PC12 cells stained with Golgi-P (20 μM). λex=633 nm, collected at 720 nm-800 nm. (A-C) Images of PC12 cells without glutamate-stimulated. (E-G) Images of glutamate-stimulated PC12 cells. (D) Fluorescence intensity output of Golgi-P in A and E. (H) The level of BDNF of these cells in A and E.

To further investigate Golgi-P could work well in neural cells, we then explored the polarity changes in PC12 cells stimulated with excess glutamate which can increase polarity regulated by oxidative stress.31 Apparently, the fluorescence in glutamate-stimulated PC12 cells was weaker than in the control cells (Figure 6). This



demonstrated that the polarity of the Golgi apparatus in glutamate-stimulated cells raised compared with that in control cells. These data verify that Golgi-P can monitor polarity changes in neural cells’ Golgi apparatus. Imaging Polarity Change in Animal Models. Given NIR excitation and emission wavelengths of Golgi-P, we examined whether this probe could be used to image polarity in vivo. Increase in polarity can result from reduce in the content of proteins that alter the hydrophilicity and hydrophobicity. The neurotrophic hypothesis suggests that depression is associated with the decreased expression of BDNF which is assembled in the Golgi apparatus. Thus, we tested the polarity in the living brains of mice and analyzed the content of BDNF in brain tissues. The mice with depression-like behaviours were established by chronic unpredictable mild stress (CUMS) and separation according to references (Figure S9, S10).32 We used Golgi-P for detection of the polarity in the living brains of mice. After surgical exposure of the brain, the probe (100 μM) was directly added to the brain, and then the brain was imaged. As shown in Figure 7, the brains of mice with depressionlike behaviours exhibited about two-folds decrease in the fluorescence intensity at 810 nm than that of the controls, indicating a significant enhancement in polarity in the brain of mice with depression-like behaviours. Similar results were obtained in the brain slices (Figure S11). These results verify that Golgi-P can visualize the variation of polarity in vivo.

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the increase in polarity should be caused by reduce in BDNF. Furthermore, PC12 cells under oxidative stress also showed a decrease in BDNF (Figure 6H) and increase in polarity, pointing that oxidative damage disturbs BDNF synthesis inducing increase in Golgi polarity.33-34 All those results provide strong evidence that the reduce in content of BDNF induced by oxidative stress lead the increase in polarity of Golgi apparatus. Additionally, the expression of BDNF was significantly down-regulated in depression. Altogether, imaging polarity changes in the Golgi apparatus using GolgiP permits indication of depression.

CONCLUSION In summary, we have developed Golgi-P, an NIR fluorescent probe for visualizing the polarity of the Golgi apparatus. Golgi-P exhibits excellent selectivity and sensitivity to polarity, as well as good biocompatibility. With the help of the cysteine moiety, Golgi-P can solely aggregate into the Golgi apparatus. Moreover, Golgi-P can well indicate the polarity differences in normal and cancer cells, and track changes of polarity upon glutamatestimulation in PC12 cells. Furthermore, through in vivo imaging, we first found that the polarity of the brains in mice with depression-like behaviours was significantly higher due to decreased synthesis of BNDF in the brains. Therefore, Golgi-P can be used for in situ and nondestructive testing of the polarity of in living brains of mice with depression-like behaviours, thereby indicating the occurrence and development of depression. This work is expected to bring hope for the clinical diagnosis of depression in the future.

ASSOCIATED CONTENT Figure 7. (A) Fluorescent image of the brains of mice with depression-like behaviors (right) and control (left). n=5. λex=700 nm, collected at 720 nm-800 nm. (B) Fluorescence intensity output of Golgi-P in image A. (C) The level of BDNF in the brains of the mice in A.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Additional experimental data, including synthesis, characterization, photophysical properties, cytotoxicity, and experimental details.

AUTHOR INFORMATION Corresponding Author Figure 8. (A) Fluorescence images of PC12 cells by using small interfering RNA (siRNA) to silence BDNF gene and control (B). (C) Fluorescence intensity output of Golgi-P in A and B. (D) The level of BDNF of these cells in A and B. λex=633 nm, collected at 720 nm - 800 nm. siRNA: 5‘-UUCUCCGAACGUGUCACGUTT-3'

After the polarity imaging experiment, we measured the level of BNDF in the brain tissue using a BDNF kit (Figure 7C). The result showed that BDNF synthesis in the brains of mice with depression-like behaviours was significantly lower than the control mice, which may be an important reason leading to the increase in brain polarity. Thus, to confirm the increased polarity of Golgi apparatus was caused by the changes in BDNF. We performed BDNF gene silencing in PC12 cells by using small interfering RNA (siRNA). Compared with control cells, these cells exhibited an obvious reduction of fluorescence (Figure 8), indicating

* E-mail: [email protected]

Author Contributions ‡These authors contributed equally.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (21535004, 91753111, 21675105) and the Key Research and Development Program of Shandong Province (2018YFJH0502), National Major Scientific and Technological Special Project for “Significant New Drugs Development” (2017ZX09301030004) and the Natural Science Foundation of Shandong Province of China (ZR2017ZC0225).

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Golgi Apparatus Polarity Indicates Depression-like Behaviours of Mice

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