Non-selective NSAIDs improve the amyloid-β-mediated suppression of memory and synaptic plasticity

Mohammadpour, Jafar Doost; Hosseinmardi, Narges; Janahmadi, Mahyar; Fathollahi, Yaghoub; Motamedi, Fereshteh; Rohampour, Kambiz

doi:10.1016/j.pbb.2015.02.012

Cited by 32 publications

(12 citation statements)

References 47 publications

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“…There is growing evidence that synaptic dysfunction and degeneration contribute to the deterioration of memory performance [ 43 , 44 ]. In the two-way ANOVA, we found that LPS and galantamine significantly affected synaptic proteins including SYN (LPS, F = 21.010, P < 0.001; galantamine, F 1,16 = 4.713, P = 0.045) and PSD-95 (LPS, F 1,16 = 78.366, P < 0.001; galantamine, F 1,16 = 16.830, P = 0.001).…”

Section: Resultsmentioning

confidence: 99%

Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice

Liu

Zhang

Zheng

et al. 2018

J Neuroinflammation

210

105

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BackgroundNeuroinflammation plays an important role in the onset and progression of neurodegenerative diseases such as Alzheimer’s disease. Lipopolysaccharide (LPS, endotoxin) levels are higher in the brains of Alzheimer’s disease patients and are associated with neuroinflammation and cognitive decline, while neural cholinergic signaling controls inflammation. This study aimed to examine the efficacy of galantamine, a clinically approved cholinergic agent, in alleviating LPS-induced neuroinflammation and cognitive decline as well as the associated mechanism.MethodsMice were treated with galantamine (4 mg/kg, intraperitoneal injection) for 14 days prior to LPS exposure (intracerebroventricular injection). Cognitive tests were performed, including the Morris water maze and step-through tests. mRNA expression of the microglial marker (CD11b), astrocytic marker (GFAP), and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were examined in the hippocampus by quantitative RT-PCR. The inflammatory signaling molecule, nuclear factor-kappa B (NF-κB p65), and synapse-associated proteins (synaptophysin, SYN, and postsynaptic density protein 95, PSD-95) were examined in the hippocampus by western blotting. Furthermore, NF-κB p65 levels in microglial cells and hippocampal neurons were examined in response to LPS and galantamine.ResultsGalantamine treatment prevented LPS-induced deficits in spatial learning and memory as well as memory acquisition of the passive avoidance response. Galantamine decreased the expression of microglia and astrocyte markers (CD11b and GFAP), pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and NF-κB p65 in the hippocampus of LPS-exposed mice. Furthermore, galantamine ameliorated LPS-induced loss of synapse-associated proteins (SYN and PSD-95) in the hippocampus. In the in vitro study, LPS increased NF-κB p65 levels in microglia (BV-2 cells); the supernatant of LPS-stimulated microglia (Mi-sup), but not LPS, decreased the viability of hippocampal neuronal cells (HT-22 cells) and increased NF-κB p65 levels as well as expression of pro-inflammatory cytokines (IL-1β, IL-6) in HT-22 cells. Importantly, galantamine reduced the inflammatory response not only in the BV-2 microglia cell line, but also in the HT-22 hippocampal neuronal cell line.ConclusionsThese findings indicate that galantamine could be a promising treatment to improve endotoxin-induced cognitive decline and neuroinflammation in neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice

Liu

Zhang

Zheng

et al. 2018

J Neuroinflammation

210

105

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“…This indicates that, unlike selective COX2 inhibitors or other NSAIDs that do not acetylate COX2, aspirin is unique in that it not only is able to inhibit the pro-inflammatory pathway but also triggers formation of SPMs. A recent study has also reported that aspirin treatment led to positive results in an AD mouse model 37 . However, aspirin use in AD patient has indicated no effect on pathology 38 .…”

Section: Discussionmentioning

confidence: 97%

Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer’s Disease

et al. 2018

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Although many reports have revealed the importance of defective microglia-mediated amyloid β phagocytosis in Alzheimer’s disease (AD), the underlying mechanism remains to be explored. Here we demonstrate that neurons in the brains of patients with AD and AD mice show reduction of sphingosine kinase1 (SphK1), leading to defective microglial phagocytosis and dysfunction of inflammation resolution due to decreased secretion of specialized proresolving mediators (SPMs). Elevation of SphK1 increased SPMs secretion, especially 15-R-Lipoxin A4, by promoting acetylation of serine residue 565 (S565) of cyclooxygenase2 (COX2) using acetyl-CoA, resulting in improvement of AD-like pathology in APP/PS1 mice. In contrast, conditional SphK1 deficiency in neurons reduced SPMs secretion and abnormal phagocytosis similar to AD. Together, these results uncover a novel mechanism of SphK1 pathogenesis in AD, in which impaired SPMs secretion leads to defective microglial phagocytosis, and suggests that SphK1 in neurons has acetyl-CoA-dependent cytoplasmic acetyltransferase activity towards COX2.

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“…Importantly, salsalate, a prodrug of salicylate, inhibits p300 acetyltransferase activity, blocks the acetylation of tau, and restores memory deficits in FTLD‐tau mice , supporting the possibility of p300 as a therapeutic target. Another study showed that treatment with sodium salicylate restored Aβ‐induced synaptic and memory deficits in rats , supporting the therapeutic potential of salsalate for AD. Salsalate did not prevent neurodegeneration in mice expressing an acetyl‐tau mimic , suggesting that the reduction of ac‐tau is an important mechanism in salsalate's protective effect.…”

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confidence: 86%

“…In addition to reducing ac‐tau levels, treatment with salsalate could alter other molecular pathways that ameliorate cognitive decline. Salsalate may restore synaptic deficits by inhibiting cyclooxygenase , a protein that is upregulated in AD . Moreover, salsalate is a non‐steroidal anti‐inflammatory drug and may be protective due to its anti‐inflammatory effects .…”

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confidence: 99%

Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss

Tracy

Gan

2017

BioEssays

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Summary Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274 and K281, which are associated with dementia in Alzheimer’s disease (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long-term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity-dependent recruitment of postsynaptic AMPA-type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory-associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD.

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Non-selective NSAIDs improve the amyloid-β-mediated suppression of memory and synaptic plasticity

Cited by 32 publications

References 47 publications

Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice

Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice

Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer’s Disease

Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss

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