Ras inhibitor S-trans, trans-farnesylthiosalicylic acid enhances spatial memory and hippocampal long-term potentiation via up-regulation of NMDA receptor

Wang, Ya; Chen, Tingting; Yuan, Zihao; Zhang, Yajie; Zhang, Baofeng; Zhao, Liandong; Chen, Ling

doi:10.1016/j.neuropharm.2018.03.026

Cited by 10 publications

(10 citation statements)

References 46 publications

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Section: Discussionsupporting

confidence: 92%

“…A recent study has reported for the first time that the RAS inhibitor, FTS, could improve the spatial memory of AD mice to some extent 18. Consistent with the previous study, our results show that FTS significantly improved spatial learning and memory detected by the MWM test in Aβ 1-42 mice after 18 days of the treatment with FTS 18. Physical exercise can increase the tolerance of cells and tissues to oxidative stress, vascularization, energy metabolism, and neurotrophin synthesis, which are beneficial for neurogenesis, memory improvement, and brain plasticity 33.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies have shown that FTS can organize abnormal cell cycle re-entry induced by soluble Aβ oligomers 13. Recently, a study has shown that the inhibition of RAS by FTS could enhance NMDAr-dependent long-term potentiation by increasing Src activity, resulting in enhanced spatial memory 18. The study focused on the effects of FTS on the survival and neurite outgrowth of Aβ-impaired neonatal neurons and explored its mechanism against AD.…”

Section: Introductionmentioning

confidence: 99%

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<p>Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease</p>

Wang¹,

Wang²,

Zhu³

et al. 2019

DDDT

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BackgroundAlzheimer’s disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aβ1-42-injected mice (Aβ1-42-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive deﬁcits.Materials and methodsAD model mice were manufactured through intracerebroventricular injection of Aβ1-42. Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot.ResultsThe results demonstrated that FTS could prevent Aβ1-42 to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in Aβ1-42-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of Aβ1-42-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by Aβ, which is the underlying molecular mechanism.ConclusionIn conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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<p>Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease</p>

Wang¹,

Wang²,

Zhu³

et al. 2019

DDDT

Self Cite

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“…Cell patch-clamp recording: AMPA-evoked currents (I AMPA ) and NMDA-evoked currents (I NMDA ) were induced in hippocampal CA1 pyramidal cells using a picospritzer (rapid drug delivery system) and recorded using an EPC-10 amplifier (HEKA Elektronik, Germany) as described (Zhou et al, 2016;Wang et al, 2018). A glass pipette was filled with an internal solution (pH 7.2) (in mM: Cs-gluconate 120, NaCl 2, MgCl 2 4, Na 2 -ATP 4, HEPES 10, EGTA 10).…”

Section: Electrophysiological Analysismentioning

confidence: 99%

“…Farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor (Kloog et al, 1999), can dislodge Ras from its anchorage domains to prevent Ras-membrane interactions (Niv et al, 2002). The administration of FTS in mice through enhancing Src activity increases GluN2A/2B phosphorylation (Wang et al, 2018). The inhibition of Ras activity restored normal spine structural plasticity and presynaptic glutamate release in Aβ-treated neurons (Ye and Carew 2010).…”

Section: Introductionmentioning

confidence: 99%

Oligomer β-amyloid Induces Hyperactivation of Ras to Impede NMDA Receptor-Dependent Long-Term Potentiation in Hippocampal CA1 of Mice

et al. 2020

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The activity of Ras, a small GTPase protein, is increased in brains with Alzheimer’s disease. The objective of this study was to determine the influence of oligomeric Aβ1-42 on the activation of Ras, and the involvement of the Ras hyperactivity in Aβ1-42-induced deficits in spatial cognition and hippocampal synaptic plasticity. Herein, we show that intracerebroventricular injection of Aβ1-42 in mice (Aβ-mice) enhanced hippocampal Ras activation and expression, while 60 min incubation of hippocampal slices in Aβ1-42 (Aβ-slices) only elevated Ras activity. Aβ-mice showed deficits in spatial cognition and NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) in hippocampal CA1, but basal synaptic transmission was enhanced. The above effects of Aβ1-42 were corrected by the Ras inhibitor farnesylthiosalicylic acid (FTS). ERK2 phosphorylation increased, and Src phosphorylation decreased in Aβ-mice and Aβ1-42-slices. Both were corrected by FTS. In CA1 pyramidal cells of Aβ1-42-slices, the response of AMPA receptor and phosphorylation of GluR1 were enhanced with dependence on Ras activation rather than ERK signaling. In contrast, NMDA receptor (NMDAR) function and GluN2A/2B phosphorylation were downregulated in Aβ1-42-slices, which was recovered by application of FTS or the Src activator ouabain, and mimicked in control slices treated with the Src inhibitor PP2. The administration of PP2 impaired the spatial cognition and LTP induction in control mice and FTS-treated Aβ-mice. The treatment of Aβ-mice with ouabain rescued Aβ-impaired spatial cognition and LTP. Overall, the results indicate that the oligomeric Aβ1-42 hyperactivates Ras and thereby causes the downregulation of Src which impedes NMDAR-dependent LTP induction resulting in cognitive deficits.

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Effects of Exercise on Long-Term Potentiation in Neuropsychiatric Disorders

Loprinzi

2020

Physical Exercise for Human Health

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Ras inhibitor S-trans, trans-farnesylthiosalicylic acid enhances spatial memory and hippocampal long-term potentiation via up-regulation of NMDA receptor

Cited by 10 publications

References 46 publications

<p>Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease</p>

<p>Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease</p>

Oligomer β-amyloid Induces Hyperactivation of Ras to Impede NMDA Receptor-Dependent Long-Term Potentiation in Hippocampal CA1 of Mice

Effects of Exercise on Long-Term Potentiation in Neuropsychiatric Disorders

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