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      Escitalopram attenuates β-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT 1A receptor mediated Akt/GSK-3β pathway

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          Abstract

          Tau hyperphosphorylation is an important pathological feature of Alzheimer's disease (AD). To investigate whether escitalopram could inhibit amyloid-β (Aβ)-induced tau hyperphosphorylation and the underlying mechanisms, we treated the rat primary hippocampal neurons with Aβ 1-42 and examined the effect of escitalopram on tau hyperphosphorylation. Results showed that escitalopram decreased Aβ 1–42-induced tau hyperphosphorylation. In addition, escitalopram activated the Akt/GSK-3β pathway, and the PI3K inhibitor LY294002 blocked the attenuation of tau hyperphosphorylation induced by escitalopram. Moreover, the 5-HT 1A receptor agonist 8-OH-DPAT also activated the Akt/GSK-3β pathway and decreased Aβ 1-42-induced tau hyperphosphorylation. Furthermore, the 5-HT 1A receptor antagonist WAY-100635 blocked the activation of Akt/GSK-3β pathway and the attenuation of tau hyperphosphorylation induced by escitalopram. Finally, escitalopram improved Aβ 1–42 induced impairment of neurite outgrowth and spine density, and reversed Aβ 1–42 induced reduction of synaptic proteins. Our results demonstrated that escitalopram attenuated Aβ 1–42-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT 1A receptor mediated Akt/GSK-3β pathway.

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          Most cited references 40

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          Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.

          We studied the accumulation of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 10 Alzheimer's disease patients who had been examined during life. We counted NFTs and SPs in 13 cytoarchitectural regions representing limbic, primary sensory, and association cortices, and in subcortical neurotransmitter-specific areas. The degree of neuropathologic change was compared with the severity of dementia, as assessed by the Blessed Dementia Scale and duration of illness. We found that (1) the severity of dementia was positively related to the number of NFTs in neocortex, but not to the degree of SP deposition; (2) NFTs accumulate in a consistent pattern reflecting hierarchic vulnerability of individual cytoarchitectural fields; (3) NFTs appeared in the entorhinal cortex, CA1/subiculum field of the hippocampal formation, and the amygdala early in the disease process; and (4) the degree of SP deposition was also related to a hierarchic vulnerability of certain brain areas to accumulate SPs, but the pattern of SP distribution was different from that of NFT.
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            Aβ(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β.

            Amyloid-β(1-42) (Aβ) is thought to be a major mediator of the cognitive deficits in Alzheimer's disease. The ability of Aβ to inhibit hippocampal long-term potentiation provides a cellular correlate of this action, but the underlying molecular mechanism is only partially understood. We found that a signaling pathway involving caspase-3, Akt1 and glycogen synthase kinase-3β is an important mediator of this effect in rats and mice.
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              Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans.

              Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonin-dependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                22 March 2016
                29 February 2016
                : 7
                : 12
                : 13328-13339
                Affiliations
                1 Department of Neurology, ZhongDa Hospital, Neuropsychiatric Institute, Medical School of Southeast University, Nanjing, China
                2 Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, China
                3 Center of Schizophrenia, Beijing Institute for Brain Disorders, Beijing, China
                Author notes
                Correspondence to: Zhi-Jun Zhang, janemengzhang@ 123456vip.163.com
                Article
                7798
                10.18632/oncotarget.7798
                4924645
                26950279
                7a9672c9-a7ee-4412-815e-b819220918b1
                Copyright: © 2016 Wang et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Research Paper: Gerotarget (Focus on Aging)

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