Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease

Decourt, Boris; Lahiri, Debomoy K.; Sabbagh, Marwan N.

doi:10.2174/1567205013666160930110551

Cited by 311 publications

(239 citation statements)

References 185 publications

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“…Decreased levels of IL-8 in patients with AD were linked to descending reparative mechanism in the central nervous system (CNS) 7. The proinflammatory cytokine TNF-α and its receptors sTNFR1 and sTNFR2, which regulate numerous physiological processes in CNS, have been detected to exacerbate the main pathological changes of AD (both Aβ and tau pathologies) in vivo 25. Our meta-analyses proved notable variances in the peripheral concentrations of sTNFR1 and sTNFR2 between group comparisons, implying that these markers may be useful in helping to monitor disease progression.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies

Shen

Niu

Wang

et al. 2019

J Neurol Neurosurg Psychiatry

291

164

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ObjectiveInflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD and MCI quantitatively.MethodsStudies reporting concentrations of peripheral or cerebrospinal fluid (CSF) markers were included, and eligible data on AD, MCI and control were extracted. Pooled Hedges’s g was adopted to illustrate comparisons, and various confounding factors were used to explore sources of heterogeneity.ResultsA total of 170 studies were included in the meta-analysis and systematic review, which demonstrated increased peripheral levels of high-sensitivity C reactive protein (Hedges’s g 0.281, p<0.05), interleukin-6 (IL-6) (0.429, p<0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p<0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p<0.005), alpha1-antichymotrypsin (α1-ACT) (1.217, p<0.005), IL-1β (0.615, p<0.05) and soluble CD40 ligand (0.868, p<0.005), and CSF levels of IL-10 (0.434, p<0.05), monocyte chemoattractant protein-1 (MCP-1) (0.798, p<0.005), transforming growth factor-beta 1 (1.009, p<0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p<0.001), YKL-40 (0.849, p<0.001), α1-ACT (0.638, p<0.001), nerve growth factor (5.475, p<0.005) and visinin-like protein-1 (VILIP-1) (0.677, p<0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p<0.05), IL-6 (0.129, p<0.05) and MCP-1 (0.779, p<0.05) and lower levels of IL-8 (−1.293, p<0.05) in the periphery, as well as elevated concentrations of YKL-40 (0.373, p<0.05), VILIP-1 (0.534, p<0.005) and sTREM2 (0.695, p<0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p<0.05) and sTNFR2 (0.254, p<0.05) levels were observed in AD compared with MCI.ConclusionSignificantly altered levels of inflammatory markers were verified in comparison between AD, MCI and control, supporting the notion that AD and MCI are accompanied by inflammatory responses in both the periphery and CSF.

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Section: Discussionmentioning

confidence: 99%

Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies

Shen

Niu

Wang

et al. 2019

J Neurol Neurosurg Psychiatry

291

164

View full text Add to dashboard Cite

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“…Furthermore, the neuropathological parameters of AD such as aggregation of phosphorylated tau protein, Aβ deposition, and activated microglial and astrocyte cell were all observed to be reduced by the inhibition of the TNF-α pathway. It's worth to mention that prevention of this signaling cascade inhibits the strong stimulation of microglial cells, keeping them in a state of moderate stimulation where they play a neuroprotective role by elevating of βAPP clearance [38].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Different Doses of Vitamine D3 in Diabetic-Induced Alzheimer Rat Model

Alzahrani

Sattar

Al-Harthi

et al. 2019

JPRI

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Background: Many studies revealed that diabetes is an independent risk factor for developing cognitive dysfunction, and Alzheimer. During diabetes, overexpression of nitric oxide, tumor necrosis factor, interleukin-6 and interleukin-1 beta could lead to Aβ accumulation and neuronal death. Aim: To examine the neuroprotective effect of different doses of vitamin D3 against diabetic-induced cognitive dysfunction in rats. Moreover, possible underlying mechanisms were also investigated. Methods: High-fat diet plus streptozotocin were used to induce diabetes in Westar rats. We sub-grouped the diabetic rats into six subgroups, positive control, vitamin D3 groups (100, 500 and 1000 IU/kg/day), vitamin D3 plus rivastigmine, and rivastigmine monotherapy. After the induction of diabetes, we started treatment for sixteen months. Morris water maze test was used to evaluate cognitive function, followed by estimation of beta-amyloid-42, inducible nitric oxide synthase, nitric oxide, tumor necrosis factor, interleukin-6, and interleukin-1β levels in the hippocampus by ELIZA kits. Results: Vitamin D3 treatment significantly (p<0.05) and dose-dependently mitigated cognitive deficits observed in Morris water maze test, with significant, suppresses in beta-amyloid-42 and nitric oxide synthase pathway via attenuated hippocampal inducible nitric oxide synthase and nitric oxide overproduction (p<0.05). Moreover, vitamin D3 decreased inflammation state of diabetic rats brains by significantly lowered (p<0.05) pro-inflammatory cytokines levels including, tumor necrosis factor, interleukin-6 and interleukin-1β as an underlying mechanism for the resulted improvement. Conclusion: The results of this research suggest that upregulation of nitric oxide synthase pathway along with the increase in pro-inflammatory cytokines is critically involved in cognitive dysfunction associated with diabetes. Vitamin D3 can ameliorate these effects and has a promising neuroprotective effect in diabetic-induced cognitive dysfunction.

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“…Further, the current analysis also showed that in older lungs, AEP and Macrophages both have TNFα levels significantly increased ( Figure 1G, Supplementary Figure S1F). Along with the gene expression signature described above, it is plausible aged baseline inflammation very likely be a result of the increased beta-amyloid load (Decourt et al, 2017). ADAM17 member of "A Disintegrin And Metalloprotease" (ADAM) family, also known as TNFα converter (TACE), mediates ACE2 shedding on the membrane in response to RAS mediated signaling (Lambert et al, 2005), was expressed in AEPs (Supplementary Figure S1G).…”

Section: Aeps(supplementarymentioning

confidence: 99%

Alveolar early progenitors in the aged human lung have increased expression of ACE2 accompanied with genes involved in beta-amyloid clearance: Indication of SARS-CoV-2 also using soluble ACE2 in aged-lungs to enter ACE2-negative cells

Chaudhri

2020

Preprint

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COVID-19 is the current pandemic caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2) that uses ACE2 protein on the cell surface. By analyzing publicly available datasets, I uncovered that alveolar early progenitors (AEP), a subset of the type-2 pneumocytes, showed increased ACE2 expression in the older lungs. AEPs co-express TMPRSS2, CTSL. Aged AEPgene expression signature suggested an active response to beta-amyloid-induced ACE2 shedding, to limit the intercellular beta-amyloid accumulation in otherwise healthy human lungs.Susceptibility of AEP to SARS-CoV2 and ACE2 secretory capacity of these cells makes aged human lung sensitive for rapid-infection, by a possible in-solution ACE2 binding and entry into ACE2-negative cells, thereby increasing the target cell diversity and numbers. Single-cell analysis of COVID19 patients with moderate and severe infections, clearly showed that severe infections showed SARS-CoV-2 transcript in ACE2-negative TMPRSS-negative but CTSLpositive cell types in their bronchoalveolar lavage fluid, validating in-solution ACE2-binding enabling infection. Since December 2019, SARS-CoV-2(COVID-19) infection, which was first reported in WuhanChina , has rapidly spread and turned into a worldwide pandemic, claiming as of May 25, 2020, more than 5.4 million infections with more than >344,000 deaths. COVID-19 has ~3-4% fatality rate (https://coronavirus.jhu.edu/map.html). COVID-19 virus belongs to the family of MER viruses, which causes infections in the human respiratory system leading to severe respiratory syndrome that can result in death. More importantly, the SARS-CoV-2 develops atypical pneumonia with a higher risk for older individuals or individuals with lung, heart, and kidney-related health issues (Shen et al., 2020), leading to a higher fatality rate accompanied by rapid progression of the respiratory syndrome and atypical pneumonia . SARS-CoV-2 binds to angiotensin-converting enzyme-2 (ACE2) binding followed by priming of spike protein S2 by transmembrane serine protease-2 (TMPRSS2) to enter the cells. Once internalized, Cathepsin L activates spike protein S, allowing the fusion of endosomal and viral membranes. A recent report has identified several epithelial cell subsets type-II pneumocyte, club cells, and ciliated cells in the lungs have ACE2, TMPRSS2 and CTSL expression. These are key genes for establishing COVID-19n infection(Hoffmann et al., 2020).Therapeutic interventions of SARS-CoV-2 needed a biological basis and possibly a mechanism of its severity. I used an analytical approach to integrate public datasets to answer the question, why the aged human population is at risk of severity and a higher fatality rate by SARS-CoV-2 ?The analysis is centered around the essential genes ACE2, TMPRSS2 and CTSL, that encodes the proteins implicated and shown to be responsible for entry to establishing the viral infection.The analysis focuses on isolating any subset of cells that are potentially altered in aged-human lungs to support SARS-CoV-2 and what is the nature of this...

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Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease

Cited by 311 publications

References 185 publications

Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies

Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies

Neuroprotective Effect of Different Doses of Vitamine D3 in Diabetic-Induced Alzheimer Rat Model

Alveolar early progenitors in the aged human lung have increased expression of ACE2 accompanied with genes involved in beta-amyloid clearance: Indication of SARS-CoV-2 also using soluble ACE2 in aged-lungs to enter ACE2-negative cells

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