Amelioration of β-amyloid-induced cognitive dysfunction and hippocampal axon degeneration by curcumin is associated with suppression of CRMP-2 hyperphosphorylation
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.
References (23)
- et al.
Collapsin response mediator protein-2 regulates neurite formation by modulating tubulin GTPase activity
Cellular Signalling
(2009) - et al.
Progressive brain dysfunction following intracerebroventricular infusion of beta(1-42)-amyloid peptide
Brain Research
(2001) - et al.
Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats
Life Sciences
(2004) - et al.
Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo
Journal of Biological Chemistry
(2005) - et al.
Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones
Molecular and Cellular Biology
(2005) - et al.
Alteration of collapsin response mediator protein-2 expression in focal ischemic rat brain
Neuroreport
(2005) - et al.
Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression
Journal of Neurochemistry
(2007) - et al.
NSAID and antioxidant prevention of Alzheimer's disease: lessons from in vitro and animal models
Annals of the New York Academy of Sciences
(2004) - et al.
Neuroprotective effects of curcumin
Advances in Experimental Medicine and Biology
(2007) - et al.
CRMP-2 binds to tubulin heterodimers to promote microtubule assembly
Nature Cell Biology
(2002)
Curcumin pretreatment prevents potassium dichromate-induced hepatotoxicity, oxidative stress, decreased respiratory complex I activity, and membrane permeability transition pore opening
Evidence-Based Complementary and Alternative Medicine: eCAM
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