Antioxidative and Neuroprotective Effects of Curcumin in an Alzheimer's Disease Rat Model Co-Treated with Intracerebroventricular Streptozotocin and Subcutaneous D-Galactose.

Epidemiological data imply links between the increasing incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both ß-cleavage of AßPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD.

Roles of O-GlcNAcylation on amyloid-ß precursor protein processing, tau phosphorylation, and hippocampal synapses dysfunction in Alzheimer's disease.

Alzheimer disease (AD), a central nervous system degenerative disease, is characterized by abnormal deposition of amyloid-ß peptide (Aß), neurofibrillary tangles formed by hyperphosphorylated tau and synaptic loss. It is widely accepted that Aß is the chief culprit of AD. Aß peptide is the cleavage product of amyloid-ß precursor protein (APP). Recently, more attention has been paid to O-linked ß-N-acetylglucosaminylation (O-GlcNAcylation) modification of protein. O-GlcNAcylation plays a significant role in hippocampal synaptic function. Abated O-GlcNAcylation might be a modulator in progression of AD through regulating activity of pertinent enzymes and factors. Evidence suggests that enhanced O-GlcNAcylation interacts with tau phosphorylation and prevents brain from tau and Aß-induced impairment. Here, we review the roles of O-GlcNAcylation in APP cleavage, tau phosphorylation and hippocampal synapses function.

Protection of curcumin against amyloid-ß-induced cell damage and death involves the prevention from NMDA receptor-mediated intracellular Ca2+ elevation.

Alzheimer's disease (AD) is one of the common neurodegenerative diseases and amyloid-ß (Aß) is thought to be a key molecule contributing to AD pathology. Recently, curcumin is supposed to be beneficial to AD treatment. This study investigates the inhibitory effects of curcumin on Aß-induced cell damage and death involving NMDA receptor-mediated intracellular Ca(2+) elevation in human neuroblastoma SH-SY5Y cells. Cells were impaired significantly in Aß-damaged group compared with the control group, and cell viability was decreased while the released LDH from the cytosol was increased. Curcumin promotes cell growth and decreases cell impairment induced by Aß. Curcmin attenuates Aß-induced elevation of the ratio of cellular glutamate/γ-aminobutyric acid (GABA) with a concentration-dependent manner. Curcumin inhibits Aß-induced increase of cellular Ca(2+) and depresses Aß-induced phosphorylations of both NMDA receptor and cyclic AMP response element-binding protein (CREB) and activating transcription factor 1 (ATF-1). These results indicated that curcumin inhibits Aß-induced neuronal damage and cell death involving the prevention from intracellular Ca(2+) elevation mediated by the NMDA receptor.

Endoplasmic reticulum stress as a novel neuronal mediator in Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common types of progressive dementias. The typical neuropathological changes in AD include extracellular senile plaques, intracellular neurofibrillary tangles, and loss of neurons. The pathogenetic mechanism of this disease is not comprehensively understood yet. Recently, endoplasmic reticulum stress (ER stress) has been considered as a potential event involved in AD development. Some AD-related factors, such as misfolded protein and Ca(2+) depletion, could disrupt the homeostasis of ER lumen. In AD, the aggregated amyloid-beta peptide (Abeta) could induce ER stress in an assembly dependent way. The presenilin has been identified as a Ca(2+) channel. Mutations of presenilin could change the balance of Ca(2+) in ER lumen and thus disrupts the ER homeostasis. Furthermore, the ER stress could lead to cellular disorders like inflammation. Through activating the expression of inflammatory factors, ER stress triggers inflammatory response in AD pathology. Herein, we reviewed the recent progress of ER stress-induced unfolded protein response (UPR) and the roles of ER stress in AD pathological process.

Chitooligosaccharides attenuate Cu2+-induced cellular oxidative damage and cell apoptosis involving Nrf2 activation.

Alzheimer's disease (AD) is one of the common neurodegenerative diseases. Increase of labile copper pool plays an important role in the pathogenesis of AD. Nrf2(NF-E2-related factor-2)-ARE (antioxidant response element) signaling is an important intracellular manner to defend against oxidative stress. In this study, we used SH-SY5Y cells as a model of neuron to test the effect of chitooligosaccharides (COSs) on Cu(2+)-induced oxidative damage. SH-SY5Y cells were treated with different concentrations of COSs (100-800 mg/L) before incubated with Cu(2+). Cell viability and cell damage and apoptosis were assessed. Both extracellular H(2)O(2) and intracellular ROS were measured and the relative levels of Nrf2, phosphorylated Nrf2, and HO-1 were analyzed by Western blotting, and further HO-1 mRNA was relatively quantified by real-time quantitative PCR. The results indicated that Cu(2+)-induced decrease of cell viability and increase of LDH release. In cell-free solution, COSs alone or with Cu(2+) cannot scavenge O(2)(-); however, COSs downregulate the levels of cellular oxidative stress and activated Caspase-3 induced by Cu(2+). Further, the levels of pSer40-Nrf2 protein and both the transcription and the translation of HO-1 gene are dramatically increased in COSs-protective group compared with Cu(2+) damage group. Therefore, these results indicate that Nrf2 activation might be involved in the protection of COSs against Cu(2+)-induced cellular oxidative damage. COSs contribute to the attenuation of oxidative damage and could be used as a nutritional agent for AD treatment.

Treatment with lutein provides neuroprotection in mice subjected to transient cerebral ischemia.

Lutein is known to be a nonprovitamin A carotenoid found in broccoli and spinach. The aim of present study was to investigate whether lutein can protect brain against ischemic injury by reducing oxidative stress. Male ICR mice were randomly divided into five experimental groups: model group, sham group, lutein high, middle, and low-dose groups (30, 15, and 7.5 mg/kg). Mice were subjected to a 2-h middle cerebral artery occlusion followed by reperfusion for 22 h. The reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, antioxidant enzyme activities, malondialdehyde (MDA), and the carbonyl content in oxidatively modified proteins in brain tissue were determined with colorimetric method. The 8-hydroxy deoxyguanosine (8-OHdG) expression was measured by immunohistochemistry assay, and the neuron apoptosis was detected by TdT-mediated dUTP nick end labeling assay. Then, the neurological deficit scores were measured at last. Treatment of lutein significantly elevated the ratio of GSH/GSSG as well as activities of superoxide dismutase, glutathione peroxidase, and catalase and obviously decreased the contents of MDA, brain carbonyl, the expression of 8-OHdG, the number of apoptotic cells, and neurological deficit scores. Our results demonstrate that administration of lutein affords strong neuroprotective effect against transient cerebral ischemic injury and that the effect might be associated with its antioxidant property.

Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer's disease.

Amyloid-beta (Abeta) peptide is the original causative factor of Alzheimer's disease (AD) according to the amyloid cascade hypothesis. The ubiquitin-proteasome system (UPS), the major intracellular protein quality control system in eukaryotic cells, is related to AD pathogenesis. There is growing evidence showing that there is a tight relationship between Abeta and UPS and this relationship plays an important role in AD pathogenesis. This article reviews the relationship between Abeta and the UPS in terms of the following three aspects: the interaction of the two factors, the ubiquitinating process of Abeta, and impact of dysfunctional UPS on Abeta production. The impairment in the UPS in AD could affect the degradation of Abeta and lead to an abnormal accumulation of Abeta. At the same time, Abeta inhibits the proteasomal activity and subsequently leads to impairment of multivesicular bodies (MVB) sorting pathway, forming an interacting relationship between Abeta and UPS. Mutant ubiquitin (Ub) and ubiquitin-like (UBL) ubiquilin-1 are related to Abeta accumulation. Meanwhile E2 conjugating enzymes, E3 ligases, and de-ubiquitinating enzymes, all of which function in the ubiquitination process, play a pivotal role in the proteasomal degradation of Abeta. Ubiquitin-proteasome system has an immense impact on the amyloidogenic pathway of amyloid precursor protein (APP) processing that generates Abeta. Upregulation in proteasomal degradation of BACE1 and components of gamma-secretase leads to decreased Abeta accumulation. A deep look into the mechanism underlying the interplay between Abeta and UPS may provide alternative therapeutic targets and lead to new drugs and therapies.

Curcumin attenuates amyloid-ß-induced tau hyperphosphorylation in human neuroblastoma SH-SY5Y cells involving PTEN/Akt/GSK-3ß signaling pathway.

Accumulated amyloid-ß peptide (Aß) and hyperphosphorylated tau proteins are two hallmarks of Alzheimer's disease (AD). Increasing evidence suggests that Aß induces tau hyperphosphorylation in AD pathology, but the signaling pathway is not completely understood. Inhibiting Aß-induced cellular signaling is beneficent to AD treatment. In this study, cellular signaling of tau phosphorylation induced by Aß and the inhibiting effects of curcumin on this signaling were investigated on human neuroblastoma SH-SY5Y cells. The results indicated that curcumin inhibits Aß-induced tau phosphorylation at Thr231 and Ser396, over-expression of HDAC6, and decrease in phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) at Ser9. However, the protective effect of curcumin on dephosphorylation of GSK-3ß induced by Aß is not directly related to cellular oxidative stress. Curcumin depresses Aß-induced down-regulation of phosphorylations of Akt at Thr308 and Ser473 and 3-phosphoinositide-dependent protein kinase 1 at Ser241, implying that second message PIP3 involves curcumin-protective cell signaling. Furthermore, insulin receptor/phosphatidyl inositol 3-kinase pathway, as a regulatory signaling of second message PIP3, does not participate in Aß-induced deactivation of Akt (dephosphorylation at Thr308 and Ser473). However, Aß results in over-expression of Phosphatase and tensin homolog (PTEN), a negative regulator of PIP3. Curcumin depresses Aß-induced up-regulation of PTEN induced by Aß. These results imply that curcumin inhibits Aß-induced tau hyperphosphorylation involving PTEN/Akt/GSK-3ß pathway.

Mitochondrial dysfunction and cellular metabolic deficiency in Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-ß (Aß) deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aß precursor protein is cleaved to produce both extracellular and intracellular Aß, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aß neurotoxicity. In this review, we summarize the pathways of Aß generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.

Curcumin-mediated neuroprotection against amyloid-ß-induced mitochondrial dysfunction involves the inhibition of GSK-3ß.

The deposition of amyloid-ß (Aß) peptides in senile plaques is one of pathological hallmarks of Alzheimer's disease (AD). Mitochondrial dysfunction is an early event of cell apoptosis. Increasing evidence indicates that Aß induces neuronal apoptosis through mitochondrial dysfunction. Curcumin, an anti-oxidative component of turmeric (Curcuma longa), has shown anti-tumor, anti-inflammatory, and anti-oxidative properties. In this study, we investigated the protective effects of curcumin against mitochondrial dysfunction induced by Aß. Based on the assay results of mitochondrial metabolic markers, we found that curcumin protects human neuroblastoma SH-SY5Y cells against the Aß-induced damage of mitochondrial energy metabolism. Curcumin inhibits Aß-induced mitochondrial depolarization of membrane potential (Δψm) and suppresses mitochondrial apoptosis-related proteins including cytochrome c, caspase-3, and Bax, which are activated by Aß. Aß-induced disturbances of redox state are linked to mitochondrial dysfunction. Curcumin normalizes cellular antioxidant enzymes (including SOD and catalase) in both protein expression and activity and decreases oxidative stress level in Aß-treated cells. Both total GSK-3ß expression and phospho-Ser9 GSK-3ß (pSer9-GSK-3ß) are down-regulated in the cells pre-treated with curcumin. This study demonstrates curcumin-mediated neuroprotection against Aß-induced mitochondrial metabolic deficiency and abnormal alteration of oxidative stress. Inhibition of GSK-3ß is involved in the protection of curcumin against Aß-induced mitochondrial dysfunction.

Protective effects of curcumin on amyloid-ß-induced neuronal oxidative damage.

To investigate the protective effects of curcumin against amyloid-ß (Aß)-induced neuronal damage. Primary rat cortical neurons were cultured with different treatments of Aß and curcumin. Neuronal morphologies, viability and damage were assessed. Neuronal oxidative stress was assessed, including extracellular hydrogen peroxide and intracellular reactive oxygen species. The abilities of curcumin to scavenge free radicals and to inhibit Aß aggregation and ß-sheeted formation are further assessed and discussed. Curcumin preserves cell viability, which is decreased by Aß. The results of changed morphology, released Lactate dehydrogenases and cell viability assays indicate that curcumin protects Aß-induced neuronal damage. Curcumin depresses Aß-induced up-regulation of neuronal oxidative stress. The treatment sequence impacts the protective effect of curcumin on Aß-induced neuronal damage. Curcumin shows a more protective effect on neuronal oxidative damage when curcumin was added into cultured neurons not later than Aß, especially prior to Aß. The abilities of curcumin to scavenge free radicals and to inhibit the formation of ß-sheeted aggregation are both beneficial to depress Aß-induced oxidative damage. Curcumin prevents neurons from Aß-induced oxidative damage, implying the therapeutic usage for the treatment of Alzheimer's disease patients.

Targeting HDACs: a promising therapy for Alzheimer's disease.

Epigenetic modifications like DNA methylation and histone acetylation play an important role in a wide range of brain disorders. Histone deacetylases (HDACs) regulate the homeostasis of histone acetylation. Histone deacetylase inhibitors, which initially were used as anticancer drugs, are recently suggested to act as neuroprotectors by enhancing synaptic plasticity and learning and memory in a wide range of neurodegenerative and psychiatric disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). To reveal the physiological roles of HDACs may provide us with a new perspective to understand the mechanism of AD and to develop selective HDAC inhibitors. This paper focuses on the recent research progresses of HDAC proteins and their inhibitors on the roles of the treatment for AD.

Amyloid-ß protein precursor family members: a review from homology to biological function.

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disease. Amyloid-ß peptide (Aß) is the most crucial molecule related to the pathological development of AD. Amyloid-ß protein precursor (AßPP) is one of AßPP family members with conserved type I transmembrane. The genetic mutations of AßPP and the abnormity of its post-transcription and proteolytic processing contribute to the elevation of Aß. The accumulation of Aß in senile plaques is believed to be the most important event in AD pathology. Therefore, as a key upstream molecule of Aß, AßPP is related to the AD pathology, but the biological function of AßPP is still not fully clear. AßPP-like proteins are widely expressed in multicellular eukaryotes. AßPP-like homologous genes and proteins are highly conserved in various organisms from invertebrates to mammals. AßPP-like genes undergo similarly pathways of transcription and post-transcription processing, and AßPP-like proteins is proteolyzed by the similar α-cleavage and the ß-cleavage pathways. Based on the homology and the resemble domains, AßPP may play similar roles in organisms. In this article, we reviewed homology and structures of AßPP family members in organisms and further discussed potential biological function in normal and AD brains.

Dual effects of curcumin on neuronal oxidative stress in the presence of Cu(II).

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders. Elevated copper (Cu) ions are thought to link AD pathology. Curcumin is suggested to treat AD because of its high anti-oxidative activity and coordination to transitional metal ions. In this study, the protective effect of curcumin against the Cu(II)-induced oxidative damage was investigated in primary rat cortical neurons. The neuronal damage was assessed by morphological observation, cell viability, and oxidative stress level. The results showed that curcumin at low dosage protected primary cultured neurons from the 20 µM Cu(II)-induced damage. Low dosage of curcumin depressed oxidative stress levels exacerbated by Cu(II). However, high dosage of curcumin failed to decrease the Cu(II)-induced oxidative stress. When Cu(II) was presented in primary neurons, curcumin at high dosage resulted in chromosomal aberration and cell damage. These results suggest that curcumin, in a concentration-dependent manner, plays both anti-oxidative and pro-oxidative roles in primary neurons treated with Cu(II).

Magnetic resonance imaging of Alzheimer's disease: from diagnosis to therapeutic evaluation.

Alzheimer's disease (AD) is a devastating late-life dementia that produces progressive loss of memory and mental faculties in elderly people. It is important to identify the earliest evidence of AD and to monitor the development of this disease for us to make positive response to its management. Magnetic resonance imaging (MRI) is powerful to image the tissue or organ without damnification. MRI can be employed to diagnose the early AD development and monitor the key biomarker development in AD. MRI may be helpful not only in diagnosing early AD, but also in evaluating its development. This article reviews the progress of MRI on the diagnosis and detection of AD, and makes comments on its therapeutic application.

Cu(II) interaction with amyloid-beta peptide: a review of neuroactive mechanisms in AD brains.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the dys-homeostasis of biometal metabolism, the extracellular accumulation of neurotoxic amyloid-beta (Abeta) peptide, the intracellular accumulation of hyperphosphorylated tau and the loss of synapses. Copper plays a key role in AD development. The Abeta peptide and amyloid precursor protein (APP), the parental molecule of Abeta, are modulated by copper in the brain. Increased copper concentration has been found in the AD brain that implies that copper may participate in the pathophysiology of AD. Copper can bind to APP and Abeta, then affects the structure and toxic of APP and Abeta. Some researchers have reported that copper could affect the formation of beta-sheet structure that is widely accepted as toxic secondary structure of Abeta. This review explores the role of copper on the conformation and aggregation of Abeta, and the copper-induced neuroactive mechanisms. Copper may be involved in the following pathways to affect the neuroactivation of Abeta: (1) change of the secondary structure of Abeta; (2) induction of oxidative stress in AD brains, and (3) regulation of cellular signal pathway. Thus, correcting brain copper imbalance may represent a relevant therapeutic target for Alzheimer's disease.

Chitooligosaccharides protect rat cortical neurons against copper induced damage by attenuating intracellular level of reactive oxygen species.

A large number of evidence has suggests that dyshomeostasis of the redox-active biometals such as copper and other metal ions can lead to oxidative stress in neurons, which plays a key role in the pathology of neurodegenerative disorders. Chitooligosaccharides (COSs) are biodegradation product of chitosan and demonstrated diverse biological activities, Here we first report that protective effects of COSs (M.W. 1500, DD. 90%) against Cu(II) induced neurotoxicity in primary cultured rat cortical neurons. The toxicity of Cu(II) to cortical neurons was obviously attenuated in a concentration-dependent manner by COSs pretreated. The data derived from lactate dehydrogenase (LDH) release and the Hoechst 33342 assay support the results from MTT assay. After DCFH assay, COSs were found to depress Cu(II) induced elevation in intracellular reactive oxygen species (ROS), These findings suggest that COSs protect against Cu(II) induced neurotoxicity in primary cortical neurons by interfering with an increase in intracellular reactive oxygen species (ROS).

Coordinating to three histidine residues: Cu(II) promotes oligomeric and fibrillar amyloid-beta peptide to precipitate in a non-beta aggregation manner.

Cu(II) has been shown in vitro to profoundly promote the aggregation of amyloid-beta peptide (Abeta), a key pathological event in Alzheimer's disease. We investigated both the effect of Cu(II) on the secondary structure transformation of Abeta and the probable residues involved in the chelation to Cu(II). The effects of Cu(II) on Abeta was analyzed by the circular dichroism spectra, Th-T fluorescence and sedimentation assay, and the results indicated that Cu(II) could disrupt the already formed beta-sheet structure, convert beta-sheeted aggregates into non-beta-sheeted aggregates and promote oligomeric Abeta to precipitate in a non-beta-sheeted aggregation way. Additionally, we confirmed that the function of Cu(II) discussed above was achieved through its interaction with His6, His13, and His14 by investigating an Abeta mutant, (23,6,13,14)Abeta(1-40).

Accumulated amyloid-beta peptide and hyperphosphorylated tau protein: relationship and links in Alzheimer's disease.

The neuropathology associated with Alzheimer's disease (AD) is characterized by the presence of extracellularly neuritic plaques, intracellularly neurofibrillary tangles and the loss of basal forebrain cholinergic neurons. The neuritic plaque is composed of a core of amyloid-beta peptide (Abeta) while the neurofibrillary tangles contain phosphorylated tau protein, and, as such, both Abeta and tau are important molecules associated with AD. In healthy human bodies, clearance mechanisms for Abeta are available; yet if clearance fails, Abeta accumulates, increasing the risk of neurotoxicity in the brain. Tau, one of the main microtubule-associated proteins, will be hyperphosphorylated and lose the ability to bind microtubules when the homeostasis of phosphorylation and dephosphorylation is disturbed in neurons. Accumulated Abeta and hyperphosphorylated tau are thought to be coexistent. Research on the pathological changes in AD indicates that accumulated Abeta in vivo may initiate the hyperphosphorylation of tau. Also, the signal transduction pathways of tau hyperphosphorylation may be related to accumulated Abeta. In this review, we will discuss how Abeta accumulates, how tau protein is hyperphosphorylated, and how accumulated Abeta initiates hyperphosphorylation of tau protein in AD.

Attenuated cytotoxicity but enhanced betafibril of a mutant amyloid beta-peptide with a methionine to cysteine substitution.

Amyloid-beta peptide (Abeta), the major constituent of senile plaques in the Alzheimer's disease (AD) brain, is the main source of oxidative stress leading to neurodegeneration. The methionine residue in this peptide is reported to be responsible for neurotoxicity. Structurally similar substitution with methionine 35 replaced by cysteine in Abeta(40) was synthesized, and this result in enhanced beta-sheet structures according to both circular dichroism (CD) spectra and beta-fibril specific fluorescence assay but attenuated cytotoxicity whether in the presence of copper or not. These findings may provide further evidence on disclosing the connection between amyloid beta-aggregation and Abeta-induced neurotoxicity.