修剪神经纤维缠结

Tau protein (encoded by the MAPT gene) is an attractive therapeutic target for the treatment of Alzheimer’s disease (AD) and other “tauopathies”, where aggregated tau pathology accumulates in neurons. Since tau deposition is strongly associated with cognitive dysfunction in AD, and tau purportedly mediates the toxicity of β-amyloid, therapies developed to reduce tau or its phosphorylation have been tested preclinically and in several small-scale clinical trials[1]. However, caveats for tau-targeting therapy include the limited understanding of its physiological functions and the complicated interactions between its post-translational modifications, aggregation, and cellular toxicity.

Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion

Ischemic stroke represents a significant danger to human beings,especially the elderly.Interventions are only available to remove the clot,and the mechanism of neuronal death during ischemic stroke is still in debate.Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs.

Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis

While many drugs are effective at reducing the relapse frequency of multiple sclerosis (MS), there is an unmet need for treatments that slow neurodegeneration resulting from secondary disease progression. The mechanism of neurodegeneration in MS has not yet been established. Here, we discovered a potential pathogenetic role of ferroptosis, an iron-dependent regulated cell death mechanism, in MS. We found that critical ferroptosis proteins (acyl-CoA synthetase long-chain family member 4, ACSL4) were altered in an existing genomic database of MS patients, and biochemical features of ferroptosis, including lipid reactive oxygen species (ROS) accumulation and mitochondrial shrinkage, were observed in the experimental autoimmune encephalitis (EAE) mouse model. Targeting ferroptosis with ferroptosis inhibitors or reducing ACSL4 expression improved the behavioral phenotypes of EAE mice, reduced neuroinflammation, and prevented neuronal death. We found that ferroptosis was an early event in EAE, which may promote T-cell activation through T-cell receptor (TCR) signaling in vitro and in vivo. These data indicate that ferroptosis may be a potential target for treating MS.

Transferrin protects against Parkinsonian neurotoxicity and is deficient in Parkinson’s substantia nigra

Iron deposition in Parkinson’s disease(PD)is a potential disease-modifying target.We previously showed that supplementation of the iron-exporter,ceruloplasmin,selectively corrected nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)model.Ceruloplasmin delivers iron to transferrin(Tf),the extracellular iron-transporting protein.We show that Tf protein levels are decreased in the nigra of post-mortem PD brains compared with controls(−35%;n=10 each).Because Tf traffics iron away from iron-replete tissues,we hypothesized that Tf supplementation could selectively facilitate iron export from the nigra in PD.In cultured neurons,Tf treatment corrected iron accumulation,and subcutaneous Tf to mice ameliorated iron accumulation and motor deficits in the MPTP model of PD.Although these data support a role for Tf in the disease mechanism for PD,and its potential use for correcting disorders of iron overload,Tf therapy also caused systemic iron depletion,which could limit its application for PD.