Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis.

The chemokine fractalkine modulates microglial responses in neurodegenerative diseases, including tauopathies, but the mechanistic processes and their relevance in human brain pathologies is not yet known. Here, we show that hippocampal HT22 cells expressing human TAU(P301L) mutant protein produce fractalkine, which in microglia activates AKT, inhibits glycogen synthase kinase-3β and upregulates the transcription factor NRF2/NFE2L2 and its target genes including heme oxygenase 1. In a mouse model of tauopathy based on stereotaxic delivery in hippocampus of an adeno-associated viral vector for expression of TAU(P301L), we confirmed that tau-injured neurons express fractalkine.

Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis.

The transcription factor NF-E2-related factor 2 (Nrf2) is a master regulator of a genetic program, termed the phase 2 response, that controls redox homeostasis and participates in multiple aspects of physiology and pathology. Nrf2 protein stability is regulated by two E3 ubiquitin ligase adaptors, Keap1 and β-TrCP, the latter of which was only recently reported. Here, two-dimensional (2D) gel electrophoresis and site-directed mutagenesis allowed us to identify two serines of Nrf2 that are phosphorylated by glycogen synthase kinase 3β (GSK-3β) in the sequence DSGISL.

α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease.

Although α-synuclein (α-SYN) aggregation is a hallmark of sporadic and familial Parkinson's disease (PD), it is not known how it contributes to early events of PD pathogenesis such as oxidative and inflammatory stress. Here, we addressed this question in a new animal model based on stereotaxic delivery of an adeno-associated viral vector (rAAV) for expression of human α-SYN in the ventral midbrain of mice lacking the transcription factor Nrf2 (Nrf2(-/-)). Two months after surgery, Nrf2(-/-) mice exhibited exacerbated degeneration of nigral dopaminergic neurons and increased dystrophic dendrites, reminiscent of Lewy neurites, which correlated with impaired proteasome gene expression and activity.

Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice.

Background: Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential.

Methods: We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.

Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism.

Current therapies for motor symptoms of Parkinson's disease (PD) are based on dopamine replacement. However, the disease progression remains unaffected, because of continuous dopaminergic neuron loss. Since oxidative stress is actively involved in neuronal death in PD, pharmacological targeting of the antioxidant machinery may have therapeutic value.

Different susceptibility to the Parkinson's toxin MPTP in mice lacking the redox master regulator Nrf2 or its target gene heme oxygenase-1.

Background: The transcription factor Nrf2 (NF-E2-related factor 2) and its target gene products, including heme oxygenase-1 (HO-1), elicit an antioxidant response that may have therapeutic value for Parkinson's disease (PD). However, HO-1 protein levels are increased in dopaminergic neurons of Parkinson's disease (PD) patients, suggesting its participation in free-iron deposition, oxidative stress and neurotoxicity. Before targeting Nrf2 for PD therapy it is imperative to determine if HO-1 is neurotoxic or neuroprotective in the basal ganglia.

Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease.

Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegeneration. The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be involved. We have addressed this question in Nrf2-knockout mice, with hypersensitivity to oxidative stress, submitted to daily inoculation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 weeks.

Role of microglial redox balance in modulation of neuroinflammation.

Purpose Of Review: This review discusses some of the emerging concepts on how modulation of redox homeostasis in microglia is crucial to restore its inactive state and modulate inflammation in neurologic diseases.

Recent Findings: Reactive oxygen species generated by microglia help to eliminate pathogens in the extracellular milieu but also act on microglia itself, altering the intracellular redox balance and functioning as second messengers in induction of proinflammatory genes. Recent findings indicate that restoration of redox balance may be determinant in driving microglia back to the resting state.

The transcription factor Nrf2 is a therapeutic target against brain inflammation.

Because chronic neuroinflammation is a hallmark of neurodegenerative diseases and compromises neuron viability, it is imperative to discover pharmacologic targets to modulate the activation of immune brain cells, the microglia. In this study, we identify the transcription factor Nrf2, guardian of redox homeostasis, as such target in a model of LPS-induced inflammation in mouse hippocampus. Nrf2 knockout mice were hypersensitive to the neuroinflammation induced by LPS, as determined by an increase in F4/80 mRNA and protein, indicative of an increase in microglial cells, and in the inflammation markers inducible NO synthase, IL-6, and TNF-alpha, compared with the hippocampi of wild-type littermates.