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Abstract

Hyperlipidemia has been demonstrated to evoke Alzheimer disease (AD) pathologies such as Amyloid-β (Aβ) deposition and synaptogenesis dysfunction in the hippocampus. Curcumin gives protection against anti-amyloid properties and synaptogenesis dysfunction. Curcumin-Nicotinate (CurTn), a new type of curcumin derivative, ameliorates cognitive impairment by rescuing autophagic flux in the CA1 hippocampus of diabetic rats. However, whether Curtn possesses an antagonistic effect on AD-related pathologies in the hippocampus induced by hyperlipidemia remains ill-defined. The present study aims to investigate whether CurTn alleviates synaptogenesis dysfunction by promoting the activation of brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB)/cAMP-response element binding protein (CREB) signaling and whether the underlying fundamental mechanism involves the elimination of Aβ deposition due to Idol/low-density lipoprotein receptor (LDLR) signaling in the hippocampus of high-fat diet (HFD)-induced hyperlipidemia rats. The results demonstrated that CurTn not only improved synaptogenesis dysfunction in the hippocampus of HFD rats, as evidenced by the increases in the expressions of synapse-related proteins postsynaptic density protein 95 (PSD-95), synapsin-1, and Glutamate receptor 1 (GluR1), but also activated BDNF/TrkB/CREB signaling, as evidenced by the elevation of the expressions of BDNF, pTrkB, and CREB. Moreover, CurTn modulated the Idol/LDLR pathway in the hippocampus of HFD rats, as evidenced by the decreased expression of Idol and the increased expression of LDLR. Furthermore, CurTn eliminated the deposition of Aβ, as evidenced by the reduction in the content of Aβ40 and Aβ42. These results reveal that CurTn may attenuate synaptogenesis dysfunction by activating BDNF/TrkB/CREB signaling, as the possible result of the modulation of Idol/LDLR signaling to eliminate Aβ deposition in the hippocampus of HFD rats.

Keywords

hyperlipidemia high-fat diet Curcumin-Nicotinate amyloid-β BDNF/TrkB/CREB signaling synaptogenesis Idol/LDLR pathway

Introduction

Previous studies revealed that hyperlipemia accelerates Alzheimer disease (AD)–related pathology,^1–3 such as Aβ deposition and synaptogenesis dysfunction in the hippocampus, as well as cognitive dysfunction.^4,5 Meanwhile, long-term consumption of a high-fat diet (HFD), a common protocol to develop the hyperlipidemia model, has also been found to have an aggravating role in Amyloid-β (Aβ) accumulation and synaptogenesis dysfunction.^1,6 Curcumin (Curcumin, C₂₁H₂₀O₆) is the principal active substance of turmeric,⁷ the lipid-lowering and anti-inflammatory effects of which have been confirmed.^8–10 In addition, there is ample evidence that curcumin has anti-amyloid properties in vivo¹⁰ and a promotive role in neurogenesis and synaptogenesis.¹¹ Curcumin-nicotinate (CurTn) is a novel curcumin derivative derived from nicotinate and curcumin, with excellent water solubility and bioavailability¹² and a more protective effect on the cell damage induced by HFD compared with curcumin.¹³ CurTn not only lowers serum low-density lipoprotein cholesterol (LDL-C) levels in apoE^−/− mice¹⁴ but also more importantly ameliorates cognitive impairment in diabetic rats by rescuing autophagic flux in the CA1 of the hippocampus.¹⁵ Therefore, the present study was to investigate whether CurTn attenuates the HFD-induced Aβ deposition and synaptogenesis dysfunction, and so it was essential to explore the underlying mechanism of CurTn.

Brain-derived neurotrophic factor (BDNF)/tyrosine-protein kinase B (TrkB)/cAMP-response element binding protein (CREB) signaling is essential for the differentiation, survival, and maintenance of neurons and regulates synaptogenesis.¹⁶ Previous studies have publicized that an impaired BDNF/TrkB/CREB pathway results in synaptogenesis dysfunction.¹⁷ In addition, activation of the BDNF/TrkB/CREB signaling pathway produces a protective effect on synaptogenesis dysfunction.^18,19 Nevertheless, activation of the BDNF/TrkB/CREB signaling pathway, and whether it is involved in the ameliorative role of CurTn on the synaptogenesis dysfunction in the hippocampus of HFD rats remains elusive.

The LDLR receptor (LDLR) is involved in receptor-mediated endocytosis to remove low-density lipoprotein (LDL) and cholesterol.²⁰ The inducible degradation agent of LDLR (Idol), an E3 ubiquitin ligase, is known to trigger the degradation of LDLR.²¹ Treatment for eliminating Idol has been found to have a significant role in harnessing hyperlipidemia.^22,23 In addition, the expression of LDLR in the brain tissue is higher in Idol^-/- mice, which further reduces Aβ deposition.²⁴ Moreover, CurTn treatment significantly increased liver LDLR expression in HFD rats.¹⁴ Thus, we speculated that CurTn may attenuate synaptogenesis dysfunction in the hippocampus of HFD-induced hyperlipidemic rats by activating BDNF/TrkB/CREB signaling, which may be associated with the elimination of Aβ deposition via the activation of Idol/LDLR signaling.

In the present study, treatment with CurTn modulated Idol/LDLR signaling, reduced Aβ deposition, and activated BDNF/TrkB/CREB signaling, as well as alleviating synaptogenesis dysfunction in the hippocampus of HFD-induced hyperlipidemic rats. Our results reveal that CurTn may be a potential therapeutic agent for Aβ deposition and synaptogenesis dysfunction induced by hyperlipidemia.

Methods

Subject

Male Wistar rats (6-7 weeks old, weighing 160-190 g) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. Rats were bred and maintained in a specific pathogen-free (SPF) environment under controlled conditions (12 h light/dark cycle; 17-27 °C; 40%-60% relative humidity). The rats were allowed to eat and drink freely, and the conditions were such as to minimize the stimulus of the external environment; adaptation to the environment lasted for 1 week. All experiments were conducted in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Best efforts were made to minimize the number of animals used and their suffering.

Reagents

Curcumin-Nicotinate (CurTn, purity > 98%) was synthesized by the Pharmacology and Phytochemical Laboratory of Hunan University of Traditional Chinese Medicine. Anti-BDNF antibody and anti-LDL Receptor antibody were purchased from Abcam, MILIP/Idol Polyclonal antibody from Absin (Absin Bioscience Inc.), anti-p-TrkB antibody and anti-TrkB antibody from Sigma (Sigma), MGluR1 Rabbit mAb, PSD95 antibody, Synapsin-1 antibody, p-CREB antibody, and CREB antibody from Cell Signaling Technology, β-actin antibody and goat anti-rabbit antibody from Proteintech (Proteintechgroup Inc.), and Rat Aβ1-40 and Rat Aβ1-42 ELISA Kits from CUSABIO (Cusabio Biotech Co., Ltd).

Drugs and Treatments

After 1 week of adaptive feeding, the rats were fed either a normal diet or HFD for 8 weeks according to different groups. During HFD administration, rats received CurTn (50, 100, and 150 mg/kg; once a day; intragastric administration) for 8 weeks. The rats were randomly divided into 5 groups: (1) control; (2) HFD; (3) HFD + a low-dose CurTn (50 mg/kg/d; HFD + L group); (4) HFD + a medium-dose CurTn (100 mg/kg/d; HFD + M group), and (5) HFD + a high-dose CurTn (150 mg/kg/d; HFD + H group). The high-fat diet consisted of a mixture of 1% cholesterol, 5% lard, and 94% standard normal feed. CurTn was given by artificial gavage. At the end of 8 weeks, the hippocampus tissues were taken to observe various indicators.

Preparation of Rat Hippocampus Homogenate

Rats were anesthetized with 5% isoflurane, the hippocampus was quickly removed, and the tissue was placed on ice to separate the hippocampus. A certain amount of hippocampus was weighed into a clean tissue grinding tube (ice bath), to which was added 9 times the amount of normal saline, 5 times the amount of cell lysate, and PMSF (PMSF: cell lysate = 1:100) (Beyotime Biological Co., Ltd) and ground thoroughly. The grinding tube was inserted into ice and lysis continued for 30 min before the liquid was pipetted into an EP tube. After centrifugation at 12 000 g at 4 °C for 10 min, the supernatant was placed in another EP tube. The protein concentration of each sample was determined with a BCA protein quantification kit (Beyotime). The remaining supernatant was labeled and stored in a refrigerator at −80 °C.

Western Blot Analysis

The expressions of IDOL, LDLR, PSD-95, Synapsin-1, GluR1, BDNF, p-TrkB, TrkB, p-CREB, and CREB in the hippocampus were detected using Western blot analysis. Proteins (25 μg/well) were separated on 10% to 12% SDS-PAGE and transferred to PVDF membranes (IPVH00010, Merck Millipore). After blocking with Tris-Buffered saline Tween (TBST, 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 0.05% Tween-20) containing either 5% skim milk or 5% BSA for 2 h at room temperature, the PVDF membrane was incubated overnight with the primary antibodies against Idol (1:1000 dilution), LDLR (1:1000 dilution), PSD-95 (1:1000 dilution), Synapsin-1 (1:1000 dilution), GluR1 (1:1000 dilution), BDNF (1:1000 dilution), p-TrkB (1:1000 dilution), TrkB (1:1000 dilution), p-CREB (1:1000 dilution), CREB (1:1000 dilution), and β-actin (1:2000 dilution) on a shaker in a 4 °C refrigerator. After 3 washes with TBST, the membranes were incubated with a secondary antibody (1:5000) diluted in either 5% skim milk or 5% BSA for 2 h at room temperature. The PVDF membrane was then washed with TBST twice again. Finally, protein bands were visualized under the gel imaging system (Tanon-5600). The integrated optical density for the protein band was measured by Image-J software.

ELISA Analysis of Aβ40 and Aβ42

The levels of amyloid beta peptide Aβ40 and Aβ42 in the hippocampus were detected by enzyme-linked immunosorbent assay kits (Cusabio Biotech Co., Ltd). The assays were performed according to the instructions of the manufacturer.

Statistical Analysis

All data in this experiment were statistically analyzed by SPSS 20. 0 Software. The data were expressed as mean ± standard error (mean ± SEM), and differences between groups were determined by one-way ANOVA: the least significant difference test (LSD t test). P < .05 was used to determine whether the differences were statistically significant.

Results

CurTn Counteracts Synaptogenesis Dysfunction in the Hippocampus of HFD Rats

To explore the antagonistic effect of CurTn on synaptogenesis dysfunction in HFD rats, the expression of synaptogenesis-related proteins PSD-95, synapsin-1, and GluR1 were detected by Western blotting. Results demonstrated that PSD-95 (Figure 1A), Synapsin-1 (Figure 1B), and GluR1 (Figure 1C) were reduced in the hippocampus of HFD rats compared with the control group. Treatment with CurTn (50 or 100 or 150 mg/kg/d) significantly increased the expressions of PSD-95 (Figure 1A), Synapsin-1 (Figure 1B), and GluR1 (Figure 1C) in the hippocampus of HFD rats compared with the HFD group. These data indicated that CurTn counteracts synaptogenesis dysfunction in the hippocampus of HFD rats.

Figure 1.

Effects of CurTn on synaptogenesis dysfunction in the hippocampus of HFD rats. Rats were treated with HFD and CurTn (0, 50, 100, and 150 mg/kg/d, i.g.) for 8 weeks. The expressions of PSD-95 (A), Synapsin-1 (B), and Glu R1 (C) were analyzed by Western blotting. β-actin was used as the control for protein loading. Values are means ± SEM n = 3. *P < .05 and **P < .01 versus control group; ^##P < .01 and ^###P < .001 versus HFD group.

CurTn Activates the BDNF/TrkB/CREB Pathway in the Hippocampus of HFD Rats

To determine whether the BDNF/TrkB/CREB pathway is involved when CurTn is used to counteract synaptogenesis dysfunction in the hippocampus of HFD rats, we observed the effect of CurTn on the expression of BDNF, p-TrkB, and p-CREB in the hippocampus of HFD rats. We found that the expression of BDNF (Figure 2A), p-TrkB (Figure 2B), and p-CREB (Figure 2C) were significantly reduced compared to the control group, and there was no significant difference in the expression of total TrkB (Figure 2B) and total CREB (Figure 2C). However, the expressions of BDNF (Figure 2A), p-TrkB (Figure 2B), and p-CREB (Figure 2C) in the hippocampus of HFD rats were increased significantly by treatment with CurTn (50 or100 or 150 mg/kg/d). These results indicated that CurTn activates the BDNF/TrkB/CREB pathway in the hippocampus of HFD rats.

Figure 2.

Effects of CurTn on the BDNF/TrkB/CREB pathway in the hippocampus of HFD rats. Rats were treated with HFD and CurTn (0, 50, 100, and 150 mg/kg/d, i.g.) for 8 weeks. The expressions of BDNF (A), p-TrkB (B), and p-CREB (C) were analyzed by Western blotting. β-actin was used as the control for protein loading. Values are means ± SEM n = 3. *P < .05 versus control group; ^#P < .05 and ^##P < .01 versus HFD group.

CurTn Eliminates Aβ Deposition in the Hippocampus of HFD Rats

To investigate whether CurTn eliminates Aβ deposition in the hippocampus of HFD rats, the contents of Aβ40 and Aβ42 were examined using an Aβ ELISA kit. The contents of Aβ40 (Figure 3A) and Aβ42 (Figure 3B) were significantly higher than those of the control group. When treated with CurTn (100 or 150 mg/kg/d), the contents of Aβ40 (Figure 3A) and Aβ42 (Figure 3B) were decreased compared with the HFD group. The results reveal that CurTn eliminates Aβ deposition in the hippocampus of HFD rats.

Figure 3.

Effects of CurTn on Aβ deposition in the hippocampus of HFD rats. Rats were treated with HFD and CurTn (0, 50, 100, and 150 mg/kg/d, i.g.) for 8 weeks. The contents of Aβ40 and Aβ42 were analyzed using Aβ ELISA kits. Values are exhibited as means ± SEM. n = 3. *P < .05 versus control group; ^#P < .05 and ^##P < .01 versus HFD group.

CurTn Reduces the Expression of Idol and Upregulates LDLR in the Hippocampus of HFD Rats

It has been shown that reduced Idol facilitates the uptake and clearance of Aβ by an increase in the expression of the low-density lipoprotein receptor (LDLR).²⁵ To explore whether CurTn-elimination of Aβ deposition in the hippocampus of HFD rats involved modulation of the Idol-LDLR pathway, we detected the effects of CurTn on the expression of Idol and LDLR in the hippocampus of HFD rats. Western blotting results showed that the expression level of Idol (Figure 4A) was increased significantly, while the content of LDLR (Figure 4B) was decreased compared with the control group, which was significantly reversed by the treatment of CurTn. These data uncovered that CurTn modulates the Idol-LDLR pathway in the hippocampus of HFD rats.

Figure 4.

Effect of CurTn on Idol/LDLR signaling pathway in the hippocampus of HFD rats. Rats were treated with HFD and CurTn (0, 50, 100, and 150 mg/kg/d, i.g.) for 8 weeks. The expression of Idol (A) and LDLR (B) in the hippocampus was detected by Western blotting. β-actin was used as the control for protein loading. Values are means ± SEM. n = 3. *P < .05 and **P < .01 versus control group; ^#P < .05, ^##P < .01, and ^###P < .001 versus HFD group.

Discussion

It has been well established that hyperlipidemia is crucial for triggering AD pathological changes such as Aβ deposition and synaptogenesis dysfunction in the brain.^26,27 Curcumin has anti-amyloid properties in vivo¹⁰ and promotes neurogenesis and synaptogenesis.¹¹ Our previous studies have proved that CurTn, a novel curcumin derivative derived from nicotinate and curcumin, has better water solubility and bioavailability than curcumin.¹⁵ In addition, CurTn decreases serum low-density lipoprotein cholesterol (LDL-C) levels and subsequent increases in LDL receptor expression in hepatocytes, serving as a potential novel compound to treat hyperlipidemia.¹⁴ More importantly, CurTn ameliorates cognitive impairment in diabetic rats by rescuing autophagic flux in the CA1 hippocampus.¹⁵ Therefore, the present work was to investigate whether CurTn exerts an antagonistic effect on the Aβ deposition and synaptogenesis dysfunction in the hippocampus of HFD rats.

Synaptogenesis is a process of forming synapses involving the formation and precise arrangement of electrical or chemical signals between presynaptic neurons and postsynaptic target cells.²⁸ Synaptogenesis dysfunction is a prominent early feature of AD.²⁹ PSD-95, the major scaffolding protein of the glutamatergic synapse, is an important participant to regulate synaptic functional plasticity and synaptic content.^30–32 Synapsin-1 is mainly expressed in neurons and plays a vital role in the formation of mature synapses during cell development.^33,34 GluR1 (Glutamate receptor1), one of the ionotropic glutamate receptors’ important subunits, is of great significance for synapse formation and retention of spatial memory.³⁵ PSD-95, Synapsin-1, and GluR1 are commonly used endogenous marker proteins in the study of synaptogenesis.^36,37 This work reveals that HFD markedly decreased the expression of PSD-95, Synapsin-1, and GluR1, indicating that HFD leads to synaptogenesis dysfunction. However, CurTn treatment increased the expression of PSD-95, Synapsin-1, and GluR1 in HFD rats, indicating that CurTn reverses synaptogenesis dysfunction in the hippocampus of HFD rats. Multiple studies have found that the BDNF/TrkB/CREB pathway is essential for synaptogenesis.^38,39 Our results showed that HFD reduced the protein levels of BDNF, p-TrkB, and p-CREB in the hippocampus, while CurTn treatment restored the expression levels of BDNF, p-TrkB, and p-CREB in the hippocampus of HFD rats. Therefore, we concluded that CurTn may attenuate synaptogenesis dysfunction by abolishing the HFD-induced inhibition of the BDNF/TrkB/CREB pathway and ultimately play a role in antagonizing AD pathology in HFD rats.

Next, we investigated the mechanism by which CurTn alleviated the inhibitory effect of HFD on the BDNF/TrkB/CREB pathway. Aβ deposition is the uppermost pathological hallmark of AD.⁴⁰ HFD treatment induced Aβ deposition in the brain of mice, which reappeared when HFD was removed.²⁷ Studies have shown a strong association between Aβ deposition and the BDNF/TrkB/CREB pathway. The aggregation of Aβ inhibits the BDNF/TrkB/CREB pathway, leading to impaired synaptogenesis.^41–43 Consistent with these studies, the present study demonstrated that the contents of Aβ40 and Aβ42 were higher in the hippocampus of HFD rats, and the treatment with CurTn reduced the accumulation of this Aβ deposition. These results indicated that CurTn may reactivate the HFD-inhibited BDNF/TrkB/CREB pathway in the hippocampus of rats by eliminating Aβ deposition.

It is reported that the E3 ubiquitin ligase Idol targets LDLR for degradation, thereby increasing Aβ amyloidosis.²⁴ Furthermore, LDLR overexpression in the brain enhances Aβ clearance as well as decreases Aβ deposition.⁴⁴ Importantly, Curtn treatment significantly increased liver LDLR expression in HFD rats.¹⁴ The present study found that the expression of Idol was significantly increased, while the expression of LDLR was decreased in HFD rats, which was reversed by the treatment with CurTn, indicating that CurTn may eliminate Aβ deposition due to the modulation of Idol/LDLR signaling in the hippocampus of HFD rats. This result suggested that CurTn may promote the elimination of Aβ deposition and then exert its anti-synaptogenesis dysfunction effect.

It is also important to note the limitation of our approach. Our present work still lacks experimental evidence to confirm that CurTn modulated Aβ levels and synaptic function through the BDNF/TrkB/CREB and Idol/LDLR pathways, only providing a preliminary conclusion to guide our research directions to consummate our hypothesis in the future. More importantly, previous studies provide the corresponding evidence. Multiple studies have found that the BDNF/TrkB/CREB pathway is essential for synaptogenesis^38,39 and the aggregation of Aβ inhibits the BDNF/TrkB/CREB pathway, leading to impaired synaptogenesis.^41–43 Moreover, LDLR overexpression in the brain enhances Aβ clearance as well as decreases Aβ deposition.⁴⁴ Importantly, our previous study demonstrates that CurTn treatment significantly increased liver LDLR expression in HFD rats.¹⁴ Together, CurTn may regulate synaptogenesis and Aβ levels through these pathways. In future experiments, we will harness various methods to activate or inhibit BDNF/TrkB/CREB and Idol/LDLR pathways to confirm that CurTn modulated synaptogenesis and Aβ levels through these pathways.

In summary, we manifested that CurTn rescues synaptogenesis dysfunction via the activation of BDNF/TrkB/CREB signaling, which may involve eliminating Aβ deposition due to the modulation of the Idol/LDLR pathway in the hippocampus of HFD rats. Therefore, CurTn may provide a new therapeutic candidate drug for the prevention and treatment of AD pathology caused by HFD.

Conclusion

CurTn rescues synaptogenesis dysfunction via activation of BDNF/TrkB/CREB signaling, which may involve eliminating Aβ deposition due to the modulation of the Idol/LDLR pathway in the hippocampus of HFD rats.

Footnotes

Acknowledgment

The authors thank Professor Duan-Fang Liao of the Hunan University of Chinese Medicine for proving Curcumin-Nicotinate.

Authors’ Note

Ethical approval was obtained from the Ethics Committee of the University of South China. All animal experiments were approved by the Animal Research Committee of the University of South China. All authors have approved the manuscript and agreed to submission to the journal. The datasets and primary data in this study are available from the corresponding author upon reasonable request.

Authors’ Contributions

L.Y.W. wrote the manuscript; J.L. and Y.Z.P. were responsible for the experiments; C.P.Z. provided experimental materials; W.Z. gave the resource; F.L. reviewed the manuscript; K.B.Z. provided formal analysis; and P.Z. gave the resource and decisive comments. All authors read and approved the final manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Natural Science Foundation of Hunan Province, Clinical Medical Technology Innovation Guidance Project of Hunan Province (grant number 2020JJ4553, 2020SK51908).

ORCID iD

Ping Zhang

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Curcumin-Nicotinate Attenuates Hippocampal Synaptogenesis Dysfunction in Hyperlipidemia Rats by the BDNF/TrkB/CREB Pathway: Involving Idol/LDLR Signaling to Eliminate Aβ Deposition

Abstract

Keywords

Introduction

Methods

Subject

Reagents

Drugs and Treatments

Preparation of Rat Hippocampus Homogenate

Western Blot Analysis

ELISA Analysis of Aβ40 and Aβ42

Statistical Analysis

Results

CurTn Counteracts Synaptogenesis Dysfunction in the Hippocampus of HFD Rats

CurTn Activates the BDNF/TrkB/CREB Pathway in the Hippocampus of HFD Rats

CurTn Eliminates Aβ Deposition in the Hippocampus of HFD Rats

CurTn Reduces the Expression of Idol and Upregulates LDLR in the Hippocampus of HFD Rats

Discussion

Conclusion

Footnotes

Acknowledgment

Authors’ Note

Authors’ Contributions

Declaration of Conflicting Interests

Funding

ORCID iD

References