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.

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-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.

The deposition of amyloid-β (Aβ) 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 Aβ 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 Aβ. Based on the assay results of mitochondrial metabolic markers, we found that curcumin protects human neuroblastoma SH-SY5Y cells against the Aβ-induced damage of mitochondrial energy metabolism. Curcumin inhibits Aβ-induced mitochondrial depolarization of membrane potential (Δψm) and suppresses mitochondrial apoptosis-related proteins including cytochrome c, caspase-3, and Bax, which are activated by Aβ. Aβ-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 Aβ-treated cells. Both total GSK-3β expression and phospho-Ser9 GSK-3β (pSer9-GSK-3β) are down-regulated in the cells pre-treated with curcumin. This study demonstrates curcumin-mediated neuroprotection against Aβ-induced mitochondrial metabolic deficiency and abnormal alteration of oxidative stress. Inhibition of GSK-3β is involved in the protection of curcumin against Aβ-induced mitochondrial dysfunction.

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

Alzheimer's disease is characterized by the abnormal aggregation of amyloid-beta peptide (Abeta) in extracellular deposits known as senile plaques. However, the nature of the toxic Abeta species and its precise mechanism of action remain unclear. Previous reports suggest that the histidine residues are involved in copper-Abeta interaction, by which resulting in the neurotoxicity of Abeta and free radical damage. Here, we employed a mutant Abeta (Abeta H13R) in which a histidine residue was replaced by arginine. Copper facilitated the precipitation of both wild-type and mutant Abeta in the spectrophotometric absorbance assay but suppressed beta-structure aggregates according to Thioflavine-T assay. Wild-type Abeta alone is more cytotoxic but produced less amount of H(2)O(2) than AbetaH13R-copper complexes, suggesting that Abeta-membrane interaction may also implicated in the pathologic progress. Abeta toxicity is in positive correlation to its competence to aggregate despite the aggregation is mainly composed of non-beta fibril substances. In short, these findings may provide further evidence on the role of copper in the pathogenesis of Alzheimer's disease.

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