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      Neuroprotective effects of salidroside through PI3K/Akt pathway activation in Alzheimer’s disease models

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          Abstract

          Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by deposits of aggregated amyloid-β (Aβ) peptide and neurofibrillary tangles in the brain parenchyma. Despite considerable research to elucidate the pathological mechanisms and identify therapeutic strategies for AD, effective treatments are still lacking. In the present study, we found that salidroside (Sal), a phenylpropanoid glycoside isolated from Rhodiola rosea L., can protect against Aβ-induced neurotoxicity in four transgenic Drosophila AD models. Both longevity and locomotor activity were improved in Sal-fed Drosophila. Sal also decreased Aβ levels and Aβ deposition in brain and ameliorated toxicity in Aβ-treated primary neuronal culture. The neuroprotective effect of Sal was associated with upregulated phosphatidylinositide 3-kinase (PI3K)/Akt signaling. Our findings identify a compound that may possess potential therapeutic benefits for AD and other forms of neurodegeneration.

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          Most cited references 25

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          Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43).

          To learn about the carboxy-terminal extent of amyloid beta-protein (A beta) composition of senile plaques (SPs) in the brain affected with Alzheimer's disease (AD), we employed two end-specific monoclonal antibodies as immunocytochemical probes: one is specific for A beta 40, the carboxyl terminus of A beta 1-40, while the other is specific for A beta 42(43). In the AD cortex, all SPs that were labeled with an authentic antibody were A beta 42(43) positive, while only one-third of which, on the average, were A beta 40 positive. There was a strong correlation between A beta 40 positivity and mature plaques. Two familial AD cortices with the mutation of beta-amyloid protein precursor 717 (beta APP717) (Val to Ile) showed a remarkable predominance of A beta 42(43)-positive, A beta 40-negative plaques. Diffuse plaques, representing the earliest stage of A beta deposition, were exclusively positive for A beta 42(43), but completely negative for A beta 40.
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            Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells.

            Beta-amyloid (Abeta) peptide, the hallmark of Alzheimer's disease (AD), invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. In this study, salidroside (Sald), an active compound isolated from a traditional Chinese medicinal plant, Rhodiola rosea L., was investigated to assess its protective effects and the underlying mechanisms against Abeta-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Abeta(25-35)-induced neuronal toxicity was characterized by the decrease of cell viability, the release of lactate dehydrogenase (LDH), morphological alterations, neuronal DNA condensation, and the cleavage of poly(ADP-ribose) polymerase (PARP) by activated caspase-3. Pretreatment with salidroside markedly attenuated Abeta(25-35)-induced loss of cell viability and apoptosis in a dose-dependent manner. The mechanisms of salidroside protected neurons from oxidative stress included the induction of antioxidant enzymes, thioredoxin (Trx), heme oxygenase-1 (HO-1), and peroxiredoxin-I (PrxI); the downregulation of pro-apoptotic protein Bax and the upregulation of anti-apoptotic protein Bcl-X(L). Furthermore, salidroside dose-dependently restored Abeta(25-35)-induced loss of mitochondrial membrane potential (MMP) as well as suppressed the elevation of intracellular reactive oxygen species (ROS) level. It was also observed that Abeta(25-35) stimulated the phosphorylation of mitogen-activated protein (MAP) kinases, including c-Jun NH(2)-terminal kinase (JNK) and p38 MAP kinase, but not extracellular signal-regulated kinase1/2 (ERK1/2). Salidroside inhibited Abeta(25-35)-induced phosphorylation of JNK and p38 MAP kinase, but not ERK1/2. These results suggest that salidroside has protective effects against Abeta(25-35)-induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer's Disease

              Background The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and β-amyloid (Aβ)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer's disease (AD). Methodology/Principal Findings We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous Aβ1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Aβ-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Aβ42 with mTOR. Conclusions/Significance These data support the notion that the mTOR pathway modulates Aβ-related synaptic dysfunction in AD.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                06 April 2016
                : 10
                : 1335-1343
                Affiliations
                [1 ]Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
                [2 ]Laboratory of Neurodegenerative Diseases, The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
                Author notes
                Correspondence: Shengdi Chen; Suya Sun, Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai 200025, People’s Republic of China, Email chen_sd@ 123456medmail.com.cn ; sunsuya@ 123456shsmu.edu.cn
                Article
                dddt-10-1335
                10.2147/DDDT.S99958
                4827895
                27103787
                © 2016 Zhang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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