Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening

Wood, Levi B.; Winslow, Ashley R.; Proctor, Elizabeth A.; McGuone, Declan; Mordes, Daniel A.; Frosch, Matthew P.; Hyman, Bradley T.; Lauffenburger, Douglas A.; Haigis, Kevin M.

doi:10.1038/srep16622

Cited by 67 publications

(67 citation statements)

References 56 publications

(72 reference statements)

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“…Although this kit is validated by the manufacturer for use with cerebrospinal fluid only, it has been successfully used in studies of human brain tissue (e.g., [35]). Further, all analytes were measurable in all subjects.…”

Section: Multiplex Assaymentioning

confidence: 99%

“…A Luminex MAP multiplex assay platform allowed the simultaneous measurement of those five analytes in a small sample volume (for a detailed description of this methodology, see [34]). This methodology has been used to successfully measure cytokines and inflammatory proteins in postmortem AD human brain tissue [35][36][37]. Further, this state-of-the-art technology has proven useful in delineating control and AD patients via cerebrospinal fluid levels of tau, phosphorylated tau and A␤ 42 [38].…”

Section: Introductionmentioning

confidence: 99%

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Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

Ferguson

Panos

Sloper

et al. 2017

JAD

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Abstract.Background: Alzheimer's disease (AD) presents with an earlier onset age and increased symptom severity in African Americans and Hispanics. Objective: Although the prevalence of plaques and tangles may not exhibit ethnicity-related differences, levels of neurodegenerative proteins have not been described. Methods: Here, levels of five proteins (i.e., S100B, sRAGE, GDNF, A␤ 40 , and A␤ 42 ) and the A␤ 42 /A␤ 40 ratio were measured in postmortem samples of the middle temporal gyrus (BA21) from age-matched African Americans and Caucasians with AD (n = 6/gender/ethnicity). Results: S100B levels were increased 17% in African Americans (p < 0.003) while sRAGE was mildly decreased (p < 0.09). A␤ 42 levels were increased 121% in African Americans (p < 0.02), leading to a 493% increase in the A␤ 42 /A␤ 40 ratio (p < 0.002). Analysis of GDNF levels did not indicate any significant effects. There were no significant effects of gender and no significant ethnicity with gender interactions on any analyte. Effect size calculations indicated "medium" to "very large" effects. Conclusion: S100B is typically elevated in AD cases; however, the increased levels in African Americans here may be indicative of increased severity in specific populations. Increased A␤ 42 /A␤ 40 ratios in the current study are compatible with increased disease severity and might indicate increased AD pathogenesis in African Americans. Overall, these results are compatible with a hypothesis of increased neuroinflammation in African Americans with AD.

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Section: Multiplex Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

Ferguson

Panos

Sloper

et al. 2017

JAD

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“…To confirm our findings, it is important to investigate changes in inflammatory mediators in postmortem brain tissues from AD, HPC, and ND individuals on the protein level. Wood et al [5] reported differences in mRNA and protein expression of neurotoxic cytokines in the postmortem brain samples of AD patients and controls. We examined the expression of some inflammatory mediators at the protein level, including several proteins in the complement system, TNFα, and its receptors in the brain of AD patients compared to HPC and ND individuals as shown below.…”

Section: Comparison Of Cytokine Expression Levels Between Ad Patientsmentioning

confidence: 99%

“…An important role for neuroinflammation in AD pathogenesis is supported by findings that immune receptor genes, including the triggering receptor expressed on myeloid cells 2 (TREM2) and CD33, are associated with AD [4]. Changes in cytokine expression in AD are not restricted to a single cytokine; there are widespread changes in intracellular cytokine signaling networks [5]. Amyloid β (Aβ) deposits, neurofibrillary tangles (NFTs), and neuronal degeneration are characteristic of AD and are the most likely sources of inflammation in AD brains [3,4,6].…”

Section: Introductionmentioning

confidence: 99%

Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimers Disease

Nagae

Araki

Shimoda

et al. 2016

J Clin Cell Immunol

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Inflammatory mechanisms are implicated in the pathology of Alzheimer’s disease (AD). However, it is unclear whether inflammatory alterations are a cause or consequence of neurodegeneration leading to dementia. Clarifying this issue would provide valuable insight into the early diagnosis and therapeutic management of AD. To address this, we compared the mRNA expression profiles of cytokines in the brains of AD patients with “non-demented individuals with AD pathology” and non-demented healthy control (ND) individuals. “Non-demented individuals with AD pathology” are referred to as high pathology control (HPC) individuals that are considered an intermediate subset between AD and ND. HPC represents a transition between normal aging and early stage of AD, and therefore, is useful for determining whether neuroinflammation is a cause or consequence of AD pathology. We observed that immunological conditions that produce cytokines in the HPC brain were more representative of ND than AD. To validate these result, we investigated the expression of inflammatory mediators at the protein level in postmortem brain tissues. We examined the protein expression of tumor necrosis factor (TNF)α and its receptors (TNFRs) in the brains of AD, HPC, and ND individuals. We found differences in soluble TNFα and TNFRs expression between AD and ND groups and between AD and HPC groups. Expression in the temporal cortex was lower in the AD brains than HPC and ND. Our findings indicate that alterations in immunological conditions involving TNFR-mediated signaling are not the primary events initiating AD pathology, such as amyloid plaques and tangle formation. These may be early events occurring along with synaptic and neuronal changes or later events caused by these changes. In this review, we emphasize that elucidating the temporal expression of TNFα signaling molecules during AD is important to understand the selective tuning of these pathways required to develop effective therapeutic strategies for AD.

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“…Recent evidence has incriminated excess brain tumor necrosis factor-alpha (TNF-α) in the pathogenesis of neurodegenerative states, such as AD [28]. Cerebral states characterized by TNF-α excess clearly have much pathophysiology in common.…”

Section: Introductionmentioning

confidence: 99%

Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α

et al. 2017

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It has been reported that activation of NF-κB is involved in excitotoxicity; however, it is not fully understood how NF-κB contributes to excitotoxicity. The aim of this study is to investigate if NF-κB contributes to quinolinic acid (QA)-mediated excitotoxicity through activation of microglia. In the cultured primary cortical neurons and microglia BV-2 cells, the effects of QA on cell survival, NF-κB expression and cytokines production were investigated. The effects of BV-2-conditioned medium (BCM) on primary cortical neurons were examined. The effects of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, and minocycline (MC), an inhibitor of microglia activation, on QA-induced excitotoxicity were assessed. QA-induced NF-κB activation and TNF-α secretion, and the roles of TNF-α in excitotoxicity were studied. QA at the concentration below 1 mM had no apparent toxic effects on cultured primary neurons or BV-2 cells. However, addition of QA-primed BCM to primary neurons did aggravate QA-induced excitotoxicity. The exacerbation of QA-induced excitotoxicity by BCM was partially ameliorated by inhibiting NF-κB and microglia activation. QA induced activation of NF-κB and upregulation of TNF-α in BV-2 cells. Addition of recombinant TNF-α mimicked QA-induced excitotoxic effects on neurons, and neutralizing TNF-α with specific antibodies partially abolished exacerbation of QA-induced excitotoxicity by BCM. These studies suggested that QA activated microglia and upregulated TNF-α through NF-κB pathway in microglia. The microglia-mediated inflammatory pathway contributed, at least in part, to QA-induced excitotoxicity.

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Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening

Cited by 67 publications

References 56 publications

Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimers Disease

Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α

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