Elsevier

Neuroscience Letters

Volume 557, Part B, 17 December 2013, Pages 112-117
Neuroscience Letters

Amelioration of β-amyloid-induced cognitive dysfunction and hippocampal axon degeneration by curcumin is associated with suppression of CRMP-2 hyperphosphorylation

https://doi.org/10.1016/j.neulet.2013.10.024Get rights and content

Highlights

  • Identify possible therapeutic mechanisms of curcumin.

  • Curcumin improved spatial learning in AD model rats.

  • Enhancing the CRMP-2/p-CRMP expression ratio, promoting axonal regeneration.

Abstract

The Alzheimer's disease (AD) brain is characterized by β-amyloid deposition, hyperphosphorylation of microtubule-associated proteins, formation of senile plaques and neurofibrillary tangles, and degeneration of specific neuronal populations. Collapsin response mediator protein 2 (CRMP-2) hyperphosphorylation has been implicated in AD-associated neural process regression and neurofibrillary tangle formation. Curcumin is a promising AD drug with incompletely defined therapeutic mechanisms. One possibility is that curcumin prevents β-amyloid-induced CRMP-2 hyperphosphorylation, thereby protecting against axonal regression and (or) promoting axonal regrowth. We examined spatial learning in the Morris water maze, hippocampal expression levels of CRMP-2 and phosphorylated CRMP-2 (p-CRMP-2) by Western blot, and NF-200 (an axon-specific marker) by immunohistochemistry in Sprague-Dawley rats subjected to a single intrahippocampal injection of Aβ1–40 alone or Aβ1–40 followed by curcumin (i.p. daily for 7 days). Compared to controls, spatial learning was significantly impaired in these Aβ1–40-injected AD model rats (P < 0.05). In addition, hippocampal expression levels of CRMP-2 and NF-200 were reduced while p-CRMP-2 expression was significantly enhanced (P < 0.05 for all). Overexpression of p-CRMP-2 was correlated with NF-200 underexpression (r2 = −0.67308, P < 0.05), suggesting that Aβ1–40 damaged hippocampal axons. Spatial learning deficits were reversed, CRMP-2 and NF-200 expression levels increased, and p-CRMP-2 expression reduced in curcumin-treated rats (all P < 0.05). We propose that curcumin improves spatial learning by inhibiting CRMP-2 hyperphosphorylation, thus protecting against β-amyloid-induced hippocampal damage or promoting regeneration.

Introduction

Alzheimer's disease (AD) is the most common form of dementia. Clinical features include insidious onset, gradual memory loss, cognitive dysfunction, and abnormal social behavior [3], [4], [12]. Current treatments can address specific symptoms but cannot slow progression. Curcumin, the main active ingredient of the herb Curcuma longa (turmeric), has well demonstrated anti-inflammatory, anti-tumor, and antioxidant properties. In addition, curcumin can block in vitro and in vivo formation of amyloid plaques, the histopathological hallmark of AD [1]. The antioxidant and anti-inflammatory properties of curcumin may benefit AD patients [15], while further exploration of the molecular mechanisms of these effects may define additional targets for AD treatment.

Collapsin response mediator protein-2 (CRMP-2), a downstream substrate of Rho kinase, is highly expressed in the nervous system and plays an important role in axonal growth orientation [12], [23]. Hyperphosphorylation of CRMP-2 may be a critical early event in AD progression by triggering neural process retrogression and the formation of neurofibrillary tangles [23]. In this study, we examined if CRMP-2 is a therapeutic target of curcumin. We established an animal model of AD by injecting the pathogenic Aβ1–40 fragment into the hippocampus of rats and then examined the effects of curcumin on spatial learning, hippocampal CRMP-2 and phospho-CRMP-2 expression levels, and the expression of the axonal protein NF-200.

Section snippets

Reagents and instruments

Curcumin, Aβ1–40, rabbit anti-CRMP-2, and rabbit anti-p-CRMP-2 were purchased from Sigma (St. Louis, USA) and mouse anti-neurofilament 200 (anti-NF-200) from Wuhan Boster Bioengineering (Wuhan, China). Main instruments (and suppliers) included a cerebral stereotaxic instrument and Morris water maze (Narishige; Tokyo, Japan), gel scanning imager (BIO-RAD; Samoa, USA), BS-50-type optical microscope (Olympus, Germany), and image analytical system (Beihang CM-2000B; Beijing, China).

Animals and grouping

Fifty-two

Curcumin improved spatial learning and memory in AD model rats

Rats subjected to intrahippocampal injection of Aβ1–40 (AD model rats) exhibited significant deficits in spatial learning compared to saline-injected control rats as measured by escape latency to the hidden platform in the Morris water maze (Fig. 1). Daily average escape latency was significantly longer on training days 2–5 in AD model rats compared to controls (P < 0.05, Fig. 1). Moreover, the swim path of the AD model rats often following the pool's circumference (thigmotaxis), indicating a

Discussion

Curcumin is the most important known active ingredient of Curcuma longa. It is a small lipophilic molecule (C21H20O6) that easily penetrates the blood–brain-barrier (BBB) but exhibits low neurotoxicity [18]. In fact, recent reports indicate that curcumin is a safer and more effective treatment for AD than currently available non-steroidal anti-inflammatory drugs and many antioxidants [22]. In countries with relatively high dietary curcumin consumption and extensive application in AD treatment,

Ethical approval

This study received permission from the Animal Ethics Committee of Zhengzhou University. The experimental procedures were performed in accordance with EC Directive 86/609/EEC for animal experiments.

Conflicts of interest statement

The authors declare no conflicts of interest.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 30770762). We thank Liuran, Neurology Laboratory of 148 Hospital of PLA, for technical support.

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