Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration. Systemic infection is associated with sustained worsening in many diseases of the CNS, yet the molecular and cellular relationship between infection outside the CNS and potential neuronal loss within the CNS is elusive. Activation of microglia, bone marrow-derived macrophage-like cells that function as the resident immune defense system of the brain (1), is a characteristic feature of most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, AIDS dementia complex, and amyotrophic lateral sclerosis as well as ischemia and posttraumatic brain injury (2-4). Neurotoxicity induced by ␤-amyloid or HIV proteins in mixed CNS cultures depends on the presence and activation of microglia (5, 6). Liberatore et al. (7) demonstrated in vivo that microglial inducible nitric oxide synthase plays a crucial role in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease.The evolutionarily ancient innate immune system provides the first line of host defense against a large variety of pathogens and also controls many aspects of the adaptive immune response (8). Cells of the innate immune system recognize invariant molecular structures of pathogens termed pathogen-associated molecular patterns through a series of genetically conserved and stable cell-surface receptors related to the Drosophila gene toll that thus are referred to as Toll-like receptors (TLRs) (9).TLR4 functions as the signal-transducing receptor for the endotoxin lipopolysaccharide (LPS) (10), which is a major component of the outer membrane of Gram-negative bacteria. LPS binds to the serum protein LPS-binding protein and the soluble or glycosylphosphatidylinositol-anchored CD14. This complex in turn binds to TLR4 (11) and initiates an intracellular signaling pathway that regulates gene expression through derepression of the transcriptional a...

Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.

The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of alpha- and beta-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.