Activation of SIRT1 by curcumin blocks the neurotoxicity of amyloid-β25–35 in rat cortical neurons
Introduction
Alzheimer’s disease (AD) is the most progressive neurodegenerative disorder in the elderly accompanied with eventual impairment of the cognitive function. The pathological features of AD include deposition of massive β-amyloid (Aβ) in senile plaques, abnormal tau accumulation in neurofibrillary tangles and loss of synapses and neurons [1]. Aβ is thought to play a critical role in the development and progress of AD. Lots of evidences show that Aβ-induced neurotoxicity is associated with reactive oxygen species (ROS) generation, mitochondrial dysfunction and calcium homeostasis [2], [3], [4].
Curcumin (Fig. 1A), a low molecular weight polyphenol (MW: 368.39) extracted from the yellow pigments spice plant turmeric, has been implied multiply bioactivities [5]. Curcumin exerts antioxidative properties by inhibiting pro-apoptotic factors such as Bcl-2-associated X protein (Bax) and peroxisome proliferator-activated receptor-γ (PPAR-γ) [6], [7]. Recently, a report suggests that curcumin scavenges free radicals and inhibited the formation of β-sheeted aggregation in cortical neurons [8]. Moreover, curcumin prevents the formation of Aβ aggregates and improves cognitive dysfunction in AD transgenic mice [9]. However, the underlying mechanisms of curcumin against Aβ-induced neurotoxicity are still not fully elucidated.
Silent information regulator 1 (SIRT1), a member of the sirtuin family, is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase. SIRT1 plays essential roles in regulating cellular functions and activities including stress responses, cell apoptosis and axonal degeneration [10], [11], [12]. SIRT1 activation by pretreatment of curcumin attenuates mitochondrial oxidative damage induced by myocardial ischemia reperfusion injury [13]. Regulation of SIRT1 is also involved in calorie restriction and aging [14], [15]. A growing numbers of evidences show that SIRT1 may regulate metabolic process and apoptosis in AD, and loss of SIRT1 is closely associated with the Aβ accumulation in transgenic mice [16], [17].
Based on above, we hypothesized that activation of SIRT1 participated the protection of curcumin against Aβ neurotoxicity. Here, we investigated the protective effects of curcumin against Aβ25–35 toxicity in rat cortical neurons to elucidate the underlying mechanisms via activating SIRT1.
Section snippets
Materials
Curcumin (purity > 99%), Aβ25–35, phenylmethanesulfonyl fluoride (PMSF), methyl thiazolyl tetrazolium (MTT), dimethylsulfoxide (DMSO) and poly-d-lysine were purchased from Sigma (USA). Dulbecco’s modified Eagle’s medium (DMEM), phosphatase inhibitor cocktail, Neurobasal A medium, B27 supplement and SIRT1 siRNA were obtained from Invitrogen (USA). Rabbit polyclonal primary antibodies cleaved caspase-3 and SIRT1 were purchased from Cell Signaling Technology (USA). Mouse anti-SIRT1 monoclonal
Curcumin attenuated Aβ25–35 -induced cell death in cortical neurons
After 7 days, cultured neurons were treated with curcumin at various doses for 24 h. The MTT assay showed that treatment of curcumin at 1, 5, 10 and 25 μM didn’t affect cell viability, but treatment of 50 μM curcumin accessed about 15.4% reduction of cell viability compared with the control group (Fig. 1B, P < 0.01). To determine the toxicity of Aβ25–35, cultured neurons were treated with Aβ25–35 at various doses (1–50 μM) for 24 h. The MTT assay showed that Aβ25–35 induced cortical neurons death in a
Discussion
The present study showed that curcumin significantly inhibited Aβ25–35-induced neuronal loss and apoptosis in cultured rat cortical neurons. Pretreatment of curcumin decreased the generation of ROS and increased mitochondrial membrane potential (ΔΨm) in Aβ rich milieu. Furthermore, the application of curcumin was able to attenuate the Aβ25–35-induced down-regulation of SIRT1, which was blocked by SIRT1 siRNA. In addition, pretreatment of curcumin decreased the expression Bax enhanced by Aβ25–35
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These authors contribute equally.