Type-I interferon pathway in neuroinflammation and neurodegeneration: focus on Alzheimer’s disease

Jm, Taylor; Moore, Zachery; Minter, Myles R.; Crack, Peter J

doi:10.1007/s00702-017-1745-4

Cited by 70 publications

(54 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4). These observations build on previous studies 43 suggesting that inhibition of the JAK-STAT and interferon signaling pathways might be beneficial in the context of AD.…”

Section: ' Digital Gene Expression Profiles Drug-induced Perturbatiosupporting

confidence: 86%

Machine Learning Identifies Novel Candidates for Drug Repurposing in Alzheimer’s Disease

Rodriguez

Hug

Todorov

et al. 2020

Preprint

View full text Add to dashboard Cite

Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. Repurposing can yield a useful therapeutic and also accelerate proof of concept studies that ultimately lead to a new molecular entity. We present a novel machine learning framework, DRIAD (Drug Repurposing In AD), that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD was validated on gene lists known to be associated with AD from other studies and subsequently applied to evaluate lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs were inspected for common trends among their nominal molecular targets and their "off-targets", revealing a high prevalence of kinases from the Janus (JAK), Unc-51-like (ULK) and NIMA-related (NEK) families. These kinase families are known to modulate pathways related to innate immune signaling, autophagy, and microtubule formation and function, suggesting possible disease-modifying mechanisms of action. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be evaluated in a clinical trial.

show abstract

“…4). These observations build on previous studies 43 suggesting that inhibition of the JAK-STAT and interferon signaling pathways might be beneficial in the context of AD.…”

Section: ' Digital Gene Expression Profiles Drug-induced Perturbatiosupporting

confidence: 86%

Machine Learning Identifies Novel Candidates for Drug Repurposing in Alzheimer’s Disease

Rodriguez

Hug

Todorov

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In the same study, the authors suggested that the CNS-produced interferon (IFN) activates AHR in astrocytes to suppress inflammation. Taking into account that the interferon has also been implicated in either aging or AD inflammation [21], we think that the IFN-AHR axis could also be involved in the increase of AHR in aging and AD patients. Besides this, the AHR accumulation can also be triggered by the low levels of ARNT previously reported during aging.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor in Post-Mortem Hippocampus and in Serum from Young, Elder, and Alzheimer’s Patients

Ramos-García

Orozco-Ibarra

Estudillo

et al. 2020

IJMS

View full text Add to dashboard Cite

One of the characteristics of the cerebral aging process is the presence of chronic inflammation through glial cells, which is particularly significant in neurodegeneration. On the other hand, it has been demonstrated that the aryl hydrocarbon receptor (AHR) participates in the inflammatory response. Currently, evidence in animal models shows that the hallmarks of aging are associated with changes in the AHR levels. However, there is no information concerning the behavior and participation of AHR in the human aging brain or in Alzheimer’s disease (AD). We evaluated the expression of AHR in human hippocampal post-mortem tissue and its association with reactive astrocytes by immunohistochemistry. Besides this, we analyzed through ELISA the AHR levels in blood serum from young and elder participants, and from AD patients. The levels of AHR and glial fibrillar acid protein were higher in elder than in young post-mortem brain samples. AHR was localized mainly in the cytosol of astrocytes and displayed a pattern that resembles extracellular vesicles; this latter feature was more conspicuous in AD subjects. We found higher serum levels of AHR in AD patients than in the other participants. These results suggest that AHR participates in the aging process, and probably in the development of neurodegenerative diseases like AD.

show abstract

“…McCoy et al (2006) demonstrated a role for TNF-α in vitro and in vivo in two models of PD, and they identified the possibility of delaying progressive PD by blocking TNF. Taylor, Moore, Minter, and Crack (2018) also found that type-1 interferons play important roles in the deterioration of neuro-inflammation and progression of AD. Zhao, Zhao, and Li (2013) determined that HN, which is a novel 24 amino acid peptide that protects cells against AD-related neurotoxicity, may have therapeutic potential as an anti-inflammation agent through its reduction of pro-inflammatory cytokines such as interleukin (IL)-6, IL-β, and TNF-α.…”

Section: Inflammationmentioning

confidence: 91%

“…() demonstrated a role for TNF‐α in vitro and in vivo in two models of PD, and they identified the possibility of delaying progressive PD by blocking TNF. Taylor, Moore, Minter, and Crack () also found that type‐1 interferons play important roles in the deterioration of neuro‐inflammation and progression of AD.…”

Section: Mechanism Of Neuronal Cell Death and The Effects Of Peptidesmentioning

confidence: 95%

Mechanisms of Neuroprotective Effects of Peptides Derived from Natural Materials and Their Production and Assessment

Lee

2019

Comp Rev Food Sci Food Safe

View full text Add to dashboard Cite

In this review, we provide an overview of the main mechanisms by which peptides derived from natural materials exhibit neuroprotective effects. We also review methods for the production of these peptides and various methods for determining their neuroprotective effects in vitro and in vivo. Neuroprotective peptides are closely associated with protection against apoptosis, with proteins related to the cell death/survival signaling pathway, with acetylcholine activity and with inhibition of oxidative stress and inflammation. Neuroprotective peptides derived from natural materials typically have a molecular weight below 1 kDa; they are most often derived using the extraction enzymes papain and alcalase. The neuroprotective peptides identified in the literature are mainly composed of hydrophobic amino acids with low molecular weight, with Asp and Glu at the N‐terminal position. These observations may guide the development of novel peptides with potential neuroprotective effects.

show abstract

Type-I interferon pathway in neuroinflammation and neurodegeneration: focus on Alzheimer’s disease

Cited by 70 publications

References 98 publications

Machine Learning Identifies Novel Candidates for Drug Repurposing in Alzheimer’s Disease

Machine Learning Identifies Novel Candidates for Drug Repurposing in Alzheimer’s Disease

Aryl Hydrocarbon Receptor in Post-Mortem Hippocampus and in Serum from Young, Elder, and Alzheimer’s Patients

Mechanisms of Neuroprotective Effects of Peptides Derived from Natural Materials and Their Production and Assessment

Contact Info

Product

Resources

About