Sleep-Wake Disorders in Alzheimer's Disease: A Review.

Alzheimer's disease (AD) is a multifactorial disease, and it has become a serious health problem in the world. Senile plaques (SPs) and neurofibrillary tangles (NFTs) are two main pathological characters of AD. SP mainly consists of aggregated ß-amyloid (Aß), and NFT is formed by hyperphosphorylated tau protein. Sleep-wake disorders are prevalent in AD patients; however, the links and mechanisms of sleep-wake disorders on the AD pathogenesis remain to be investigated. Here, we referred to the sleep-wake disorders and reviewed some evidence to demonstrate the relationship between sleep-wake disorders and the pathogenesis of AD. On one hand, the sleep-wake disorders may lead to the increase of Aß production and the decrease of Aß clearance, the spreading of tau pathology, as well as oxidative stress and inflammation. On the other hand, the ApoE4 allele, a risk gene for AD, was reported to participate in sleep-wake disorders. Furthermore, some neurotransmitters, such as acetylcholine, glutamate, serotonin, melatonin, and orexins, and their receptors were suggested to be involved in AD development and sleep-wake disorders. We discussed and suggested some possible therapeutic strategies for AD treatment based on the view of sleep regulation. In general, this review explored different views to find novel targets of diagnosis and therapy for AD.

Curcumin Inhibits Cell Damage and Apoptosis Caused by Thapsigargin-Induced Endoplasmic Reticulum Stress Involving the Recovery of Mitochondrial Function Mediated by Mitofusin-2.

Endoplasmic reticulum stress (ERS) and mitochondrial dysfunction have been suggested to relate with the pathology of Alzheimer's disease (AD). However, their cross-talk is needed to investigate further. Mitofusin-2 (Mfn2) is a member of mitochondria-associated membrane (MAM), which connects endoplasmic reticulum (ER) and mitochondria. This study investigated the protective effect of curcumin on thapsigargin (TG)-induced ERS and cell apoptosis and the role of Mfn2 on mitochondrial dysfunction. The cell viability of SH-SY5Y cells was decreased and cell damage and apoptosis were increased in a concentration-dependent manner when cells were treated with TG. TG upregulated the protein levels of GRP78, pSer981-PERK, and pSer51-eIF2α. Curcumin attenuated TG-induced damage on cell viability and apoptosis and downregulated the protein levels of GRP78, pSer981-PERK, and pSer51-eIF2α. TG caused the increases in intracellular reactive oxygen species (ROS) and in the protein levels of pSer40-Nrf2 and hemoglobin oxygenase 1 (HO-1). Curcumin decreased the TG-induced intracellular ROS but did not alter the protein levels of pSer40-Nrf2 and HO-1. TG resulted in the upregulation on Mfn2 expression and mitochondrial spare respiratory capacity but the downregulation on mitochondrial basal respiration and ATP production. Curcumin attenuated the TG-induced Mfn2 expression and mitochondrial stress. When Mfn2 was silenced by shRNA interference, curcumin failed to recovery the TG-damaged mitochondrial function. In general, the TG-induced ERS trigged mitochondrial dysfunction and cell apoptosis. Curcumin attenuates TG-induced ERS and the cell damage and apoptosis. Mfn2 is required for curcumin's protection against the TG-induced damage on mitochondrial functions.

Phosphorylation and Glycosylation of Amyloid-ß Protein Precursor: The Relationship to Trafficking and Cleavage in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder in the central nervous system, and this disease is characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Amyloid-ß (Aß) peptide is the main constituent of senile plaques, and this peptide is derived from the amyloid-ß protein precursor (AßPP) through the successive cleaving by ß-site AßPP-cleavage enzyme 1 (BACE1) and γ-secretase. AßPP undergoes the progress of post-translational modifications, such as phosphorylation and glycosylation, which might affect the trafficking and the cleavage of AßPP. In the recent years, about 10 phosphorylation sites of AßPP were identified, and they play complex roles in glycosylation modification and cleavage of AßPP. In this article, we introduced the transport and the cleavage pathways of AßPP, then summarized the phosphorylation and glycosylation sites of AßPP, and further discussed the links and relationship between phosphorylation and glycosylation on the pathways of AßPP trafficking and cleavage in order to provide theoretical basis for AD research.

Inhibitory effects of curcumin on H2O2-induced cell damage and APP expression and processing in SH-SY5Y cells transfected with APP gene with Swedish mutation.

Alzheimer's disease (AD) is a neurodegenerative disorder, and the pathological mechanism of the disease is still far to understand. According to the amyloid cascade hypothesis in AD, Amyloid-ß (Aß) is considered as a key substance that contributes AD development. Aß is a ß-cleaving product from Amyloid-ß protein precursor (APP). Mutations of APP including APPKM670/671670NL (Swedish mutation) result in Aß overproduction and the development of early-onset familial AD. Increase of oxidative stress and damage also occurs in early stage of AD. In this study, we used a SH-SY5Y cell line that stably expresses APP gene with Swedish mutation (SH-SY5Y-APPswe), and the inhibitory effects of curcumin on H2O2-induced cell damage and APP processing were investigated. Cells were treated with curcumin (0 ~ 5 µM) for 4 h before hydrogen peroxide (H2O2). Cell growth was detected with CCK-8 assay, and cell damage was determined through the evaluation of release of lactate dehydrogenase (LDH) from the cytosol to the culture medium and the morphological change of nucleus. The ability of mitochondrial stress and the depolarization of mitochondrial membrane potential were assayed through the measuring the oxygen consumption rate (OCR) and the green/red fluorescence ratio of JC-1 dye respectively. The protein levels of APP, sAPPα, sAPPß, and BACE1 were analyzed with Western blot assay. Aß production was measured with enzyme-linked immunosorbent assay (ELISA). The results indicated that curcumin inhibits H2O2-induced decrease of cell growth and cell damage. Curcumin attenuates H2O2-induced damage on the ability to mitochondrial oxidative phosphorylation and membrane potential. Curcumin inhibits H2O2-induced increase of APP cleavage through ß-cleavage pathway and of intracellular Aß production. These results imply that curcumin can be used to treat AD through inhibiting oxidative damage-induced APP ß-cleavage and intracellular Aß generation.