scholarly journals Proinflammatory and anti-inflammatory cytokines in the CSF of patients with Alzheimer's disease and their correlation with cognitive decline

2019 ◽  
Vol 76 ◽  
pp. 125-132 ◽  
Author(s):  
Ricardo Taipa ◽  
Sofia P. das Neves ◽  
Ana L. Sousa ◽  
Joana Fernandes ◽  
Claudia Pinto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Inflammatory Cytokines ◽  
Anti Inflammatory

Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Staley A. Brod
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Cognitive Decline ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Type I ◽  
Type I Ifn ◽  
Anti Inflammatory

Systemic inflammation is an organism’s response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer’s disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the “principal culprit” in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

scholarly journals Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Fan’ge Kong ◽  
Xue Jiang ◽  
Ruochen Wang ◽  
Siyu Zhai ◽  
Yizhi Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Tau Protein ◽  
Calcium Binding ◽  
Neuroprotective Effect ◽  
Nuclear Factor Κb ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ht22 Cells ◽  
Anti Inflammatory

Abstract Background Neuroinflammation is a principal element in Alzheimer’s disease (AD) pathogenesis, so anti-inflammation may be a promising therapeutic strategy. Forsythoside B (FTS•B), a phenylethanoid glycoside isolated from Forsythiae fructus, has been reported to exert anti-inflammatory effects. However, no studies have reported whether the anti-inflammatory properties of FTS•B have a neuroprotective effect in AD. In the present study, these effects of FTS•B were investigated using amyloid precursor protein/presenilin 1 (APP/PS1) mice, BV-2 cells, and HT22 cells. Methods APP/PS1 mice were administered FTS•B intragastrically for 36 days. Behavioral tests were then carried out to examine cognitive functions, including the Morris water maze, Y maze, and open field experiment. Immunohistochemistry was used to analyze the deposition of amyloid-beta (Aβ), the phosphorylation of tau protein, and the levels of 4-hydroxynonenal, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule 1 in the hippocampus. Proteins that showed marked changes in levels related to neuroinflammation were identified using proteomics and verified using enzyme-linked immunosorbent assay and western blot. BV-2 and HT22 cells were also used to confirm the anti-neuroinflammatory effects of FTS•B. Results In APP/PS1 mice, FTS•B counteracted cognitive decline, ameliorated the deposition of Aβ and the phosphorylation of tau protein, and attenuated the activation of microglia and astrocytes in the cortex and hippocampus. FTS•B affected vital signaling, particularly by decreasing the activation of JNK-interacting protein 3/C-Jun NH2-terminal kinase and suppressing WD-repeat and FYVE-domain-containing protein 1/toll-like receptor 3 (WDFY1/TLR3), further suppressing the activation of nuclear factor-κB (NF-κB) signaling. In BV-2 and HT22 cells, FTS•B prevented lipopolysaccharide-induced neuroinflammation and reduced the microglia-mediated neurotoxicity. Conclusions FTS•B effectively counteracted cognitive decline by regulating neuroinflammation via NF-κB signaling in APP/PS1 mice, providing preliminary experimental evidence that FTS•B is a promising therapeutic agent in AD treatment.

scholarly journals Anti-inflammatories in Alzheimer’s disease—potential therapy or spurious correlate?

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Jack Rivers-Auty ◽  
Alison E Mather ◽  
Ruth Peters ◽  
Catherine B Lawrence ◽  
David Brough
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Decline ◽  
Negative Binomial ◽  
Drug Efficacy ◽  
Therapeutic Effects ◽  
Inflammatory Drug ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Abstract Epidemiological evidence suggests non-steroidal anti-inflammatory drugs reduce the risk of Alzheimer’s disease. However, clinical trials have found no evidence of non-steroidal anti-inflammatory drug efficacy. This incongruence may be due to the wrong non-steroidal anti-inflammatory drugs being tested in robust clinical trials or the epidemiological findings being caused by confounding factors. Therefore, this study used logistic regression and the innovative approach of negative binomial generalized linear mixed modelling to investigate both prevalence and cognitive decline, respectively, in the Alzheimer’s Disease Neuroimaging dataset for each commonly used non-steroidal anti-inflammatory drug and paracetamol. Use of most non-steroidal anti-inflammatories was associated with reduced Alzheimer’s disease prevalence yet no effect on cognitive decline was observed. Paracetamol had a similar effect on prevalence to these non-steroidal anti-inflammatory drugs suggesting this association is independent of the anti-inflammatory effects and that previous results may be due to spurious associations. Interestingly, diclofenac use was significantly associated with both reduce incidence and slower cognitive decline warranting further research into the potential therapeutic effects of diclofenac in Alzheimer’s disease.

scholarly journals Electroacupuncture Improves M2 Microglia Polarization and Glia Anti-inflammation of Hippocampus in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Lushuang Xie ◽  
Yi Liu ◽  
Ning Zhang ◽  
Chenyu Li ◽  
Aaron F. Sandhu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Cytokine Expression ◽  
Tnf Α ◽  
Microglia Polarization ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by loss of recognition and memory. Neuroinflammation plays pivotal roles in the pathology of AD and affects the progression of the disease. Astrocyte and microglia, as main immune executors in the central nervous system (CNS), participate into the inflammatory response in AD. Glia polarize into different phenotypes during neurodegeneration. Pro-inflammatory glia produce cytokines (IL-1β, TNF-α, and IL-6) resulting into debris aggregates and neurotoxicity. Anti-inflammatory phenotypes produce cytokines (IL-4 and IL-10) to release the inflammation. Electroacupuncture is a useful treatment that has been found to slow the neurodegeneration in animals through experimentation and in humans through clinical trials. The aim of this study was to uncover the mechanisms of glia activation, microglia polarization, and cytokine secretion regulated by electroacupuncture as a treatment for AD.Methods: Twenty male Sprague–Dawley (SD) rats were randomly divided into four groups: Control group (Control), Normal saline group (NS), AD group (AD), and Electroacupuncture group (Acupuncture). The AD and Acupuncture groups were bilaterally injected with Aβ1–42 into the CA1 field of the hippocampus. The Acupuncture group received electroacupuncture stimulation on the acupoint “Baihui” (GV20) for 6 days per week for a total of 3 weeks. The Morris Water Maze (MWM) was used to evaluate learning and memory capacity. Immunofluorescence was used to stain GFAP and Iba1 of the DG and CA1 in the hippocampus, which, respectively, expressed the activation of astrocyte and microglia. The M1 microglia marker, inducible nitric oxide synthase (iNOS), and M2 marker Arginase 1 (Arg1) were used to analyze the polarization of microglia. The pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6), anti-inflammatory cytokines (IL-4 and IL-10), and pathway-molecules (p65 and Stat6) were tested to analyze the glia inflammatory response by immunofluorescence and polymerase chain reaction (PCR).Results: The MWM results showed that electroacupuncture improves the escape latency time and the swimming distance of AD rats. The number of GFAP and Iba1 cells significantly increased in AD rats, but electroacupuncture decreased the cells. The iNOS-positive cells were significantly increased in AD, and electroacupuncture decreased the positive cells. Electroacupuncture elevated Arg1-positive cells in AD rats. Electroacupuncture decreased the glia pro-inflammatory cytokine expression and increased the anti-inflammatory cytokine expression in AD rats. Furthermore, electroacupuncture inhibited the NF-κB pathway molecule (p65) while raising the Stat6 pathway molecule (Stat6).Conclusion: These results provide evidence that electroacupuncture improves the recognition abilities and memory of AD rats. Electroacupuncture inhibits the activation of glia and polarizes microglia toward the M2 phenotype. Electroacupuncture decreased the pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and increased the anti-inflammatory cytokines (IL-4 and IL-10). Furthermore, electroacupuncture affects the immune responses through inhibition of NF-κB pathway but activation of Stat6 pathway.

scholarly journals Anti-inflammatory Activity of a Polypeptide Fraction From Achyranthes bidentate in Amyloid β Oligomers Induced Model of Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiangyu Ge ◽  
Yitong Wang ◽  
Shu Yu ◽  
Xuemin Cao ◽  
Yicong Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Cytokines ◽  
Mrna Levels ◽  
Bv2 Microglia ◽  
M1 Phenotype ◽  
Anti Inflammatory ◽  
The Brain ◽  
M2 Phenotype ◽  
Pro Inflammatory Cytokines

Neuroinflammation plays a crucial role in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and anti-inflammation has been considered as a potential therapeutic strategy. Achyranthes bidentate polypeptide fraction k (ABPPk) was shown to protect neurons from death and suppress microglia and astrocyte activation in PD model mice. However, how ABPPk regulates neuroinflammation to exert a neuroprotective role remains unclear. Toxic Aβ oligomers (AβOs) can trigger inflammatory response and play an important role in the pathogenesis of AD. In the present study, for the first time, we investigated the effects and underlying mechanisms of ABPPk on neuroinflammation in AβOs-induced models of AD. In vitro, ABPPk pretreatment dose-dependently inhibited AβOs-induced pro-inflammatory cytokines mRNA levels in BV2 and primary microglia. ABPPk pretreatment also reduced the neurotoxicity of BV2 microglia-conditioned media on primary hippocampal neurons. Furthermore, ABPPk down-regulated the AβOs-induced phosphorylation of IκBα and NF-κB p65 as well as the expression of NLRP3 in BV2 microglia. In vivo, ABPPk pre-administration significantly improved locomotor activity, alleviated memory deficits, and rescued neuronal degeneration and loss in the hippocampus of AβOs-injected mice. ABPPk inhibited the activation of microglia in hippocampal CA3 region and suppressed the activation of NF-κB as well as the expression of NLRP3, cleaved caspase-1, and ASC in the brain after AβOs injection. ABPPk hindered the release of pro-inflammatory cytokines and promoted the release of anti-inflammatory cytokines in the brain. Notably, the polarization experiment on BV2 microglia demonstrated that ABPPk inhibited M1-phenotype polarization and promoted M2-phenotype polarization by activating the LPS- or AβOs-impaired autophagy in microglia. Taken together, our observations indicate that ABPPk can restore the autophagy of microglia damaged by AβOs, thereby promoting M2-phenotype polarization and inhibiting M1-phenotype polarization, thus playing a role in regulating neuroinflammation and alleviating neurotoxicity.

scholarly journals The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1–42)-Induced Neuroinflammation in Mouse Models of Alzheimer’s Disease

2021 ◽  
Author(s):  
Ewa Trojan ◽  
Kinga Tylek ◽  
Nicole Schröder ◽  
Iris Kahl ◽  
Lars-Ove Brandenburg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Cytokines ◽  
Ex Vivo ◽  
Neuronal Loss ◽  
Formyl Peptide Receptor ◽  
Peptide Receptor ◽  
Formyl Peptide ◽  
Anti Inflammatory

Abstract The major histopathological hallmarks of Alzheimer’s disease (AD) include β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Aβ 1–42 (Aβ1-42) has been shown to induce neurotoxicity and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of Aβ1-42 were shown to be mediated by interactions with several cell surface receptors, including the chemotactic G protein-coupled N-formyl peptide receptor 2 (FPR2). The present study investigated the impact of a new FPR2 agonist, MR-39, on the neuroinflammatory response in ex vivo and in vivo models of AD. To address this question, organotypic hippocampal cultures from wild-type (WT) and FPR2-deficient mice (knockout, KO, FPR2−/−) were treated with fibrillary Aβ1-42, and the effect of the new FPR2 agonist MR-39 on the release of pro- and anti-inflammatory cytokines was assessed. Similarly, APP/PS1 double-transgenic AD mice were treated for 20 weeks with MR-39, and immunohistological staining was performed to assess neuronal loss, gliosis, and Aβ load in the hippocampus and cortex. The data indicated that MR-39 was able to reduce the Aβ1-42-induced release of proinflammatory cytokines and to improve the release of anti-inflammatory cytokines in mouse hippocampal organotypic cultures. The observed effect was apparently related to the inhibition of the MyD88/TRAF6/NFкB signaling pathway and a decrease in NLRP3 inflammasome activation. Administration of MR-39 to APP/PS1 mice improved neuronal survival and decreased microglial cell density and plaque load.These results suggest that FPR2 may be a promising target for alleviating the inflammatory process associated with AD and that MR-39 may be a useful therapeutic agent for AD.

scholarly journals Plasma Cytokines Profile in Subjects with Alzheimer’s Disease: Interleukin 1 Alpha as a Candidate for Target Therapy

2021 ◽  
Vol 10 ◽  
pp. e1974
Author(s):  
Meisam Mahdavi ◽  
Saeed Karima ◽  
Shima Rajaei ◽  
Vajihe Aghamolaii ◽  
Hossein Ghahremani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Cytokines ◽  
Interferon Gamma ◽  
Neurodegenerative Disorder ◽  
Neuropsychiatric Symptoms ◽  
Interleukin 1 ◽  
Recent Theory ◽  
Tnf Α ◽  
Anti Inflammatory

Background: Alzheimer’s disease (AD) is the main cause of the neurodegenerative disorder, which is not detected unless the cognitive deficits are manifested. An early prediagnostic specific biomarker preferably detectable in plasma and hence non-invasive is highly sought-after. Various hypotheses refer to AD, with amyloid-beta (Aβ) being the most studied hypothesis and inflammation being the most recent theory wherein pro-and anti-inflammatory cytokines are the main culprits. Materials and Methods: In this study, the cognitive performance of AD patients (n=39) was assessed using mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), and clinical dementia rating (CDR). Their neuropsychiatric symptoms were evaluated through neuropsychiatric inventory–questionnaire (NPI-Q). Moreover, plasma levels of routine biochemical markers, pro-/anti-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1 α (IL-1α), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-12p70, IL-10, Interferon-gamma, chemokines, including prostaglandin E2 (PGE-2), monocyte chemoattractant protein-1, interferon gamma-induced protein 10, Aβ peptide species (42, 40) and Transthyretin (TTR) were measured. Results: Our results revealed that Aβ 42/40 ratio and TTR were correlated (r=0.367, P=0.037). IL-1α was directly correlated with ADAS-cog (r=0.386, P=0.017) and Aβ 40 (r=0.379, P=0.019), but was inversely correlated with IL-4 (r=-0.406, P=0.011). Negative correlations were found between MMSE and PGE2 (r=-0.405, P=0.012) and TNF-α/ IL-10 ratio (r=-0.35, P=0.037). CDR was positively correlated with both PGE2 (r=0.358, P=0.027) and TNF-α (r=0.416, P=0.013). There was a positive correlation between NPI-caregiver distress with CDR (r=0.363, P=0.045) and ADAS-cog (r=0.449, P=0.019). Conclusion: Based on the observed correlation between IL-1α, as a clinical moiety, and ADAS-cog, as a clinical manifestation of AD, anti-IL-1α therapy in AD could be suggested. [GMJ.2021;10:e1974]

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