scholarly journals Platycodigenin as Potential Drug Candidate for Alzheimer’s Disease via Modulating Microglial Polarization and Neurite Regeneration

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3207 ◽  
Author(s):  
Zhiyou Yang ◽  
Baiping Liu ◽  
Long-en Yang ◽  
Cai Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Neurons ◽  
Neuronal Survival ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Factors ◽  
Primary Microglia ◽  
Microglial Polarization ◽  
Anti Inflammatory

Neuroinflammatory microenvironment, regulating neurite regrowth and neuronal survival, plays a critical role in Alzheimer’s disease (AD). During neuroinflammation, microglia are activated, inducing the release of inflammatory or anti-inflammatory factors depending on their polarization into classical M1 microglia or alternative M2 phenotype. Therefore, optimizing brain microenvironment by small molecule-targeted microglia polarization and promoting neurite regeneration might be a potential therapeutic strategy for AD. In this study, we found platycodigenin, a naturally occurring triterpenoid, promoted M2 polarization and inhibited M1 polarization in lipopolysaccharide (LPS)-stimulated BV2 and primary microglia. Platycodigenin downregulated pro-inflammatory molecules such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and nitric oxide (NO), while upregulated anti-inflammatory cytokine IL-10. Further investigation confirmed that platycodigenin inhibited cyclooxygenase-2 (Cox2) positive M1 but increased Ym1/2 positive M2 microglial polarization in primary microglia. In addition, platycodigenin significantly decreased LPS-induced the hyperphosphorylation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 subunits. Furthermore, the inactivation of peroxisome proliferators-activated receptor γ (PPARγ) induced by LPS was completely ameliorated by platycodigenin. Platycodigenin also promoted neurite regeneration and neuronal survival after Aβ treatment in primary cortical neurons. Taken together, our study for the first time clarified that platycodigenin effectively ameliorated LPS-induced inflammation and Aβ-induced neurite atrophy and neuronal death.

scholarly journals Microglial ApoD Induced NLRC4 Inflammasome Activation Promotes Alzheimer’s Disease Progression

2021 ◽  
Author(s):  
Yaliang Yu ◽  
Jianzhou Lv ◽  
Dan Ma ◽  
Ya Han ◽  
Yaheng Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Microglia Activation ◽  
Inflammatory Factors ◽  
Inflammasome Activation ◽  
Cellular Interactions ◽  
Brain Functions ◽  
Chronic Neuroinflammation

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no effective therapies. It’s well-known that chronic neuroinflammation plays a critical role in the onset and progression of AD. Proper neuronal-microglial interactions are essential for brain functions. However, as the main existence of immune cells, determining the role of microglia in Alzheimer’s neuroinflammation and the associated molecular basis has been challenging. Herein, the inflammatory factors in the sera of AD patients were detected and the association with microglia activation was analyzed. The mechanism regarding the microglial inflammation was investigated. The IL6 and TNF-α were found to be significantly increased in the AD stage. Further analysis revealed microglia were extensively activated in AD cerebra releasing mounts of cytokines to impair the neural stem cells (NSCs) function. Moreover, ApoD induced NLRC4 inflammasome was activated in microglia, which gave rise to the proinflammatory phenotype. Targeting the microglial ApoD promoted NSCs self-renewal and inhibited neuron apoptosis. These findings demonstrate the critical role of ApoD in microglial inflammasome activation, and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation. Our studies establish the cellular basis for microglia activation in AD progression, and shed lights on cellular interactions important for AD treatment.

scholarly journals Anti-Inflammatory Gene Therapy Improves Spatial Memory Performance in a Mouse Model of Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Tai June Yoo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Therapy ◽  
Mouse Model ◽  
Spatial Memory ◽  
Memory Performance ◽  
Critical Role ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Anti Inflammatory

The immune system plays a critical role in neurodegenerative processes involved in Alzheimer’s disease (AD). In this study, a gene-based immunotherapeutic method examined the effects of anti-inflammatory cellular immune response elements (CIREs) in the amyloid-β protein precursor (AβPP) mouse model. Bi-monthly intramuscular administration, beginning at either 4 or 6 months, and examined at 7.5 through 16 months, with plasmids encoding Interleukin (IL)-10, IL-4, TGF-β polynucleotides, or a combination thereof, into AβPP mice improved spatial memory performance. This work demonstrates an efficient gene therapy strategy to downregulate neuroinflammation, and possibly prevent or delay cognitive decline in AD.

Differential effect of intranasally administrated kinin B1 and B2 receptor antagonists in Alzheimer’s disease mice

2016 ◽  
Vol 397 (4) ◽  
pp. 345-351 ◽  
Author(s):  
Keren Asraf ◽  
Nofar Torika ◽  
Ella Roasso ◽  
Sigal Fleisher-Berkovich
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Brain Inflammation ◽  
Inflammatory Factors ◽  
Receptor Antagonists ◽  
Kinin System ◽  
Necrosis Factor Alpha ◽  
Hoe 140

Abstract An Increasing body of evidence supports a critical role of brain inflammation in the pathogenesis of Alzheimer’s disease. A principal aspect of the brain immune response to inflammation is the activation of microglia. It has been shown that the kinin system is activated during brain inflammation and previously we demonstrated that bradykinin B1 receptor agonist reduced microglial activation in vitro. The aim of the present study was to investigate the effects of bradykinin B1 or B2 receptor antagonists on microglial release of pro-inflammatory factors in BV2 microglia. In vivo, we focused on the effects of intranasally given kinin antagonists on amyloid burden and microglia/macrophage marker expression in brains of 5X familial Alzheimer’s disease mice. The present data show that pharmacological antagonism of B1 receptor (R-715) but not B2 receptor (HOE-140) markedly increased nitric oxide and tumor necrosis factor alpha release from BV2 microglial cells. We also showed that intranasal treatment with R-715 but not HOE-140 of Alzheimer’s mice enhanced amyloid beta burden and microglia/macrophages activation. Taken together, our data reveal a possible role for the bradykinin B1 receptor in neuroinflammation and in the control of Abeta accumulation in transgenic mice, possibly through regulation of glial cell responses.

scholarly journals TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer’s Disease: Lessons Learned from Transcriptomics

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 321
Author(s):  
Feng Xue ◽  
Heng Du
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Critical Role ◽  
Lessons Learned ◽  
Immunoglobulin Superfamily ◽  
Missense Mutations ◽  
Anti Inflammatory ◽  
Ad Mouse Model ◽  
Shed Light

Alzheimer’s disease (AD) is a lethal neurodegenerative disorder primarily affecting the aged population. The etiopathogenesis of AD, especially that of the sporadic type, remains elusive. The triggering receptor expressed on myeloid cells 2 (TREM2), a member of TREM immunoglobulin superfamily, plays a critical role in microglial physiology. Missense mutations in human TREM2 are determined as genetic risk factors associated with the development of sporadic AD. However, the roles of TREM2 in the pathogenesis of AD are still to be established. In this review, we outlined the influence of Trem2 on balance of pro- and anti-inflammatory microglial activations from a perspective of AD mouse model transcriptomics. On this basis, we further speculated the roles of TREM2 in different stages of AD, which may shed light to the development of TREM2-targeted strategy for the prevention and treatment of this neurodegenerative disorder.

scholarly journals Recombinant Adiponectin Peptide Ameliorates Cortical Neuron Damage Induced by Chronic Cerebral Hypoperfusion by Inhibiting NF-κB Signaling and Regulating Microglial Polarization

2021 ◽  
Author(s):  
li'an Huang ◽  
Wenxian Li ◽  
Di Wei ◽  
Zheng Zhu ◽  
Shuqin Zhan ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Neuronal Survival ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Inflammatory Factors ◽  
Microglial Polarization ◽  
Neuron Damage ◽  
Bv2 Microglia ◽  
Anti Inflammatory

Abstract Background Chronic cerebral hypoperfusion (CCH) is common in multiple central nervous system diseases that are associated with neuronal death and cognitive impairment. Microglial activation-mediated polarization changes may be involved in CCH-induced neuronal damage. Adiponectin (APN) is a fat-derived plasma protein that affects neuroprotection. This study investigated whether a recombinant APN peptide (APN-P) improved the cognitive function of CCH rats by regulating microglial polarization in the cortex. Methods A CCH rat model was established through bilateral common carotid artery occlusion (BCCAO) surgery. An antibody microarray was used to analyze differentially expressed proteins in the cerebral cortex of CCH rats compared to the sham rats. APN-P and a solvent control were used to intervene at different time points. Western blotting and immunofluorescence staining were conducted to examine the status of microglial polarization in different treatment groups. qRT-PCR was used to detect the expression levels of inflammatory and anti-inflammatory genes. Neuronal morphology was assessed via Nissl staining, and cognitive function was assessed with the Morris water maze test. In vitro , by inhibiting the expression of NF-κB in BV2 microglia and using Transwell co-culture systems of BV2 microglia and neurons, the effects of APN-P on neuroprotection and the underlying mechanism were investigated. Results In the cortical microglia of 12-week-old CCH rats, the expression of APN protein was significantly downregulated compared to the sham rats. CCH damages neurons and activates cortical microglial polarization to an M1-type by upregulating inflammatory factors. APN-P supplementation upregulated APN expression in cortical microglia, with neuronal survival as well as microglial polarization from an M1 toward an M2 phenotype in CCH cortex. In vivo and in vitro experiments revealed that APN-P promoted the expression of anti-inflammatory factors and neuronal survival by inhibiting NF-κB signaling, thus improving the cognitive function in CCH rats. Conclusions Our study revealed a novel mechanism by which APN-P suppresses the NF-κB pathway and promotes microglial polarization from M1 toward the M2-type to reduce neuron damage in the cortex after CCH.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

Consideration of a Pharmacological Combinatorial Approach to Inhibit Chronic Inflammation in Alzheimer’s Disease

2019 ◽  
Vol 16 (11) ◽  
pp. 1007-1017 ◽  
Author(s):  
James G. McLarnon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Chronic Inflammation ◽  
Preventive Strategy ◽  
Subsequent Work ◽  
Activated Microglia ◽  
Starting Point ◽  
Anti Inflammatory ◽  
Cocktail Approach

A combinatorial cocktail approach is suggested as a rationale intervention to attenuate chronic inflammation and confer neuroprotection in Alzheimer’s disease (AD). The requirement for an assemblage of pharmacological compounds follows from the host of pro-inflammatory pathways and mechanisms present in activated microglia in the disease process. This article suggests a starting point using four compounds which present some differential in anti-inflammatory targets and actions but a commonality in showing a finite permeability through Blood-brain Barrier (BBB). A basis for firstchoice compounds demonstrated neuroprotection in animal models (thalidomide and minocycline), clinical trial data showing some slowing in the progression of pathology in AD brain (ibuprofen) and indirect evidence for putative efficacy in blocking oxidative damage and chemotactic response mediated by activated microglia (dapsone). It is emphasized that a number of candidate compounds, other than ones suggested here, could be considered as components of the cocktail approach and would be expected to be examined in subsequent work. In this case, systematic testing in AD animal models is required to rigorously examine the efficacy of first-choice compounds and replace ones showing weaker effects. This protocol represents a practical approach to optimize the reduction of microglial-mediated chronic inflammation in AD pathology. Subsequent work would incorporate the anti-inflammatory cocktail delivery as an adjunctive treatment with ones independent of inflammation as an overall preventive strategy to slow the progression of AD.

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