Potential therapeutic effects of curcumin: Relationship to microtubule-associated proteins 2 in Aβ1–42 insult

Abstract

Curcumin can bind senile plaques and promote disaggregation of existing amyloid deposits and prevent aggregation of new amyloid deposits. Curcumin can also reverse distorted and curvy neurites around senile plaques and repair the neuritic abnormalities. We hypothesized whether altered neurite morphologies resulting from Aβ production had anything to do with the changes of expression of microtubule-associated protein 2 (MAP2), but curcumin could reverse damaged neurites by upregulation of MAP2 expression. In present study we designed and chemically synthesized curcumin and its six derivatives. After screening the protective effect of curcumin and derivatives, we found that the viability of SK-N-SH cell model induced by Aβ1–42 was significantly increased by curcumin and Cur1, and the expression of MAP-2 protein was obviously up-regulated in immunocytochemical staining and Western blot. The cell morphologies, including the number of neurites, neurite growth and neurite extension, were significantly improved. Cur1 showed more significant protective effect on SK-N-SH cells than curcumin. Our study revealed for the first time that the neuroprotective effect of curcumin and curcumin derivatives not only directly depends on their special chemical constitution, but they can resist to Aβ damage by up-regulation of MAP-2 expression. In view of the special advantages of curcumin and Cur1, we reasonably believe that curcumin and Cur1 may be considered as an ideal therapeutic agent for the treatment of AD.

Introduction

The accumulation of amyloid-β (Aβ) and senile plaques is widely believed to contribute to pathogenesis of Alzheimer's disease (AD) (Selkoe, 2001, Hardy and Selkoe, 2002, Walsh et al., 2002). The recent studies found that curcumin could bind senile plaques in brain sections of patients with Alzheimer's disease or in a transgenic mouse model of AD. In vivo studies showed that curcumin could promote disaggregation of existing amyloid deposits and prevent aggregation of new amyloid deposits, even reduce the size of remaining deposits (Garcia-Alloza et al., 2007), and further, Kim and Park (2002) demonstrated that curcumin and curcumin derivatives could inhibit the fAβ (fibrillar β-amyloid) formation from fresh Aβ and destabilize preformed fAβ in vitro, alternatively, not only curcumin and curcumin derivatives could decrease fAβ, but reduce the stability of fAβ which led to fAβ degradation, thus curcumin plays an important role in neuroprotective effect by resistance to neurotoxicity of Aβ. On the other hand, senile plaques are associated with synaptic loss and abnormal neurite morphology (Perl, 2010), which results in a disruption of synaptic integration in AD. Curcumin can reverse distorted and curvy neurites located in the surrounding of senile plaques, and repair the neuritic abnormalities induced by Aβ insult (Garcia-Alloza et al., 2007).

Microtubule-associated protein 2(MAP2) is a neuronal cytoskeletal component, which takes part in maintaining cellular architecture and internal organization, with clear involvement of defining cell shape, in cell division and cellular processes, such as neurite extension (Yamaguchi et al., 2008). Alterations and deterioration of cytoskeleton is related to malfunction of nerve cells in brain tissue of AD (Johnson and Jope, 1992). Nukina and Ihara (1986) revealed that MAP2 monoclonal antibody could mark neurofibrillary tangles (NFTs), and MAP2 polyclonal antibody also labeled abnormal neurites around senile plaques in AD. We hypothesized whether altered neurite morphologies resulting from Aβ production had anything to do with the changes of expression of MAP2; whether curcumin could influence the expression of MAP2 lead to reversion of distorted and curvy neurites. We also wondered whether the chemical constitution of curcumin gives its certain advantages in the treatment of AD. Curcumin's compact and symmetrical phenol groups make it better brain-permeable and able to cross the blood brain barrier (Wang et al., 2010) and its compact and symmetric structure may also be suitable for specifically binding to free Aβ and subsequently inhibiting polymerization of Aβ into fAβ. The autofluorescence of curcumin may reliably label senile plaques and NFTs in AD, thus it facilitates to observe the changes of senile plaques and NFTs in brain tissue (Garcia-Alloza et al., 2007). Although the recent studies supported the evidence that curcumin could reduce plaques, and partially restore the altered neurite structure, what special chemical constitution of curcumin is responsible for its neuroprotective properties might, however, be unknown, because most of curcumin used in the study, purchased from Chemical Corporation, had the identical chemical structure. In the work reported here, we designed and chemically synthesized curcumin and six kinds of curcumin derivatives for determining the relationship between the certain chemical constitution of curcumin and neuroprotective effect. We assessed the changes of expression of MAP2 in human neuroblastoma SK-N-SH cells after treatment with curcumin and curcumin derivatives. Our study revealed for the first time that the neuroprotective effect of curcumin and curcumin derivatives not only directly depends on their special chemical constitution, but they can up-regulate the expression of MAP2 which led to resistance to Aβ damage. These results suggest that targeted modification of certain chemical constitution of curcumin would greatly improve its neuroprotective effect, by which we might develop a class of curcumin drug as treatment for Alzheimer's disease.