A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.

/pdf/curcumin-requires-tumor-necrosis-factor-a-signaling-to-503zpd8eod.pdf

Curcumin requires tumor necrosis factor α signaling to alleviate cognitive impairment elicited by lipopolysaccharide.

A single mouse click on the topic tumor necrosis factor (TNF) in PubMed reveals about 50 000 articles providing one or the other information about this pleiotropic cytokine or its relatives. This demonstrates the enormous scientific and clinical interest in elucidating the biology of a molecule (or rather a large family of molecules), which began now almost 30 years ago with the description of a cytokine able to exert antitumoral effects in mouse models. Although our understanding of the multiple functions of TNF in vivo and of the respective underlying mechanisms at a cellular and molecular level has made enormous progress since then, new aspects are steadily uncovered and it appears that still much needs to be learned before we can conclude that we have a full comprehension of TNF biology. This review shortly covers some general aspects of this fascinating molecule and then concentrates on the molecular mechanisms of TNF signal transduction. In particular, the multiple facets of crosstalk between the various signalling pathways engaged by TNF will be addressed. Cell Death and Differentiation (2003) 10, 45–65. doi:10.1038/ sj.cdd.4401189

/pdf/tumor-necrosis-factor-signaling-4agufl4zu9.pdf

Tumor necrosis factor signaling.

Over the past two decades, research has heavily emphasized basic mechanisms that irreversibly damage brain cells after stroke. Much attention has focused on what makes neurons die easily and what strategies render neurons resistant to ischaemic injury. In the past few years, clinical experience with clot-lysing drugs has confirmed expectations that early reperfusion improves clinical outcome. With recent research emphasizing ways to reduce tissue damage by both vascular and cell-based mechanisms, the spotlight is now shifting towards the study of how blood vessels and brain cells communicate with each other. This new research focus addresses an important need in stroke research, and provides challenges and opportunities that can be used to therapeutic advantage.

/pdf/mechanisms-challenges-and-opportunities-in-stroke-4b227sy4dn.pdf

Mechanisms, challenges and opportunities in stroke

1. Electron Donor 2223 2. Electron Transfer Path 2225 3. Electron Transfer Mechanism 2226 4. Physiological Relevance 2226 D. Radical Reactions in Photolyase 2226 E. “Dark Function” of Photolyase 2227 F. Regulation of Photolyase 2227 III. (6−4) Photolyase 2228 IV. Cryptochromes 2230 A. Structure 2231 B. Function 2231 1. Circadian Rythm 2231 2. Mammalian Circadian System 2231 3. Cryptochromes and the Circadian Clock 2232 V. Perspectives 2234 VI. Acknowledgment 2235 VII. References 2235

Structure and function of DNA photolyase and cryptochrome blue-light photoreceptors.

HIV-associated dementia (HAD) is an important complication of the central nervous system in patients who are infected with HIV-1. Although the incidence of HAD has markedly decreased since it has become possible to effectively control viral replication in the blood by administering highly active antiretroviral therapy, a less severe form of HAD, comprising a milder cognitive and motor disorder, is now potentially a serious problem. Brain macrophages and microglia are the key cell types that are infected by HIV-1 in the central nervous system, and they are likely to mediate the neurodegeneration seen in patients with HAD; however, the precise pathogenesis of this neurodegeneration is still unclear. Here, we discuss the studies that are being carried out to determine the respective contributions of infection, and monocyte and macrophage activation, to disease progression.

The neuropathogenesis of AIDS

Tumor necrosis factor (TNF) is an important factor in various acute and chronic neurodegenerative disorders. In retinal ischemia, we show early, transient upregulation of TNF, TNF receptor 1 (TNF-R1), and TNF-R2 6 hr after reperfusion preceding neuronal cell loss. To assess the specific role of TNF and its receptors, we compared ischemia-reperfusion-induced retinal damage in mice deficient for TNF-R1, TNF-R2, or TNF by quantifying neuronal cell loss 8 d after the insult. Surprisingly, TNF deficiency did not affect overall cell loss, yet absence of TNF-R1 led to a strong reduction of neurodegeneration and lack of TNF-R2 led to an enhancement of neurodegeneration, indicative of TNF-independent and TNF-dependent processes in the retina, with TNF-R1 augmenting neuronal death and TNF-R2 promoting neuroprotection. Western blot analyses of retinas revealed that reduction of neuronal cell loss in TNF-R1/ animals correlated with the presence of activated Akt/protein kinase B (PKB). Inhibition of the phosphatidylinositol 3-kinase signaling pathway reverted neuroprotection in TNF-R1-deficient mice, indicating an instrumental role of Akt/PKB in neuroprotection and TNF-R2 dependence of this pathway. Selective inhibition of TNF-R1 function may represent a new approach to reduce ischemia-induced neuronal damage, being potentially superior to strategies aimed at suppression of TNF activity in general.

https://www.jneurosci.org/content/jneuro/22/7/RC216.full.pdf

Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2.

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Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2.