One major component of this project involves efforts to understand the functions of toll-like receptors (TLRs)in neuronal plasticity and neurodegenerative disorders. We discovered that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-gamma stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death in stroke. Brain ischemia induces an inflammatory response involving activated complement fragments. In a preclinical study we showed that i.v. Ig (IVIG) treatment, which scavenges complement fragments, protects brain cells against the deleterious effects of experimental ischemia and reperfusion (I/R) and prevents I/R-induced mortality in mice. Animals administered IVIG either 30 min before ischemia or after 3 h of reperfusion exhibited a 50-60% reduction of brain infarct size and a 2- to 3-fold improvement of the functional outcome. Even a single low dose of IVIG given after stroke was effective. IVIG was protective in the nonreperfusion model of murine stroke as well and did not exert any peripheral effects. Human IgG as well as intrinsic murine C3 levels were significantly higher in the infarcted brain region compared with the noninjured side, and their physical association was demonstrated by immuno-coprecipitation. C5-deficient mice were significantly protected from I/R injury compared with their wild-type littermates. Exposure of cultured neurons to oxygen/glucose deprivationresulted in increased levels of C3 associated with activation of caspase 3, a marker of apoptosis;both signals were attenuated with IVIG treatment. Our data suggest a major role for complement-mediated cell death in ischemic brain injury and the prospect of using IVIG in relatively low doses as an interventional therapy for stroke. 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 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. Although vaccines that reduce A plaques can ameliorate cognitive deficits in animal models, they have failed in clinical trials due to serious side-effects. Old humans and mice usually respond poorly to vaccines due to presumably age-related immunological impairments. We found that by modifying vaccines, the poor responsiveness of old mice can be reversed. Unlike the A peptide vaccine, DNA immunizations with the amino-terminal A(1-11) fragment exposed on the surface of HBsAg particles elicit high levels of anti-A antibody both in young and old mice. Importantly, in AD model 3xTgAD mice, the vaccine reduced A plaques, ameliorated cognitive impairments and, surprisingly, significantly increased life span. Hence, we propose that vaccines targeting A(1-11) can efficiently combat AD-induced pathological alterations and provide survival benefit in patients with AD. Tumor necrosis factor-α(TNF) plays a prominent role in the brain damage and functional deficits that result from ischemic stroke. It was recently reported that the thalidomide analog 3,6'-dithiothalidomide (3,6'-DT) can selectively inhibit the synthesis of TNF in cultured cells. We therefore tested the therapeutic potential of 3,6'-DT in a mouse model of focal ischemic stroke. Administration of 3,6'-DT immediately prior to a stroke or within 3 hr after the stroke reduced infarct volume, neuronal death, and neurological deficits, whereas thalidomide was effective only when administered prior to stroke. Neuroprotection was accompanied by decreased inflammation;3,6'-DT-treated mice exhibited reduced expression of TNF, interleukin-1β, and inducible nitric oxide synthase;reduced numbers of activated microglia/macrophages, astrocytes, and neutrophils;and reduced expression of intercellular adhesion molecule-1 in the ischemic brain tissue. 3,6'-DT treatment attenuated stroke-induced disruption of the blood-brain barrier by a mechanism that appears to involve suppression of matrix metalloproteinase-9 and preservation of occludin. Treatment with 3,6'-DT did not reduce ischemic brain damage in mice lacking TNF receptors, consistent with a critical role for suppression of TNF production and TNF signaling in the therapeutic action of 3,6'-DT. These findings suggest that anti-inflammatory mechanisms underlie the therapeutic actions of 3,6-DT in an animal model of stroke. The adaptive arm of the immune system has been suggested as an important factor in brain function. However, given the fact that interactions of neurons or glial cells with T lymphocytes rarely occur within the healthy CNS parenchyma, the underlying mechanism is still a mystery. Here we found that at the interface between the brain and blood circulation, the epithelial layers of the choroid plexus (CP) are constitutively populated with CD4(+) effector memory cells with a T-cell receptor repertoire specific to CNS antigens. With age, whereas CNS specificity in this compartment was largely maintained, the cytokine balance shifted in favor of the T helper type 2 (Th2) response;the Th2-derived cytokine IL-4 was elevated in the CP of old mice, relative to IFN-γ, which decreased. We found this local cytokine shift to critically affect the CP epithelium, triggering it to produce the chemokine CCL11 shown to be associated with cognitive dysfunction. Partial restoration of cognitive ability in aged mice, by lymphopenia-induced homeostasis-driven proliferation of memory T cells, was correlated with restoration of the IL-4:IFN-γratio at the CP and modulated the expression of plasticity-related genes at the hippocampus. Our data indicate that the cytokine milieu at the CP epithelium is affected by peripheral immunosenescence, with detrimental consequences to the aged brain. Amenable to immunomodulation, this interface is a unique target for arresting age-related cognitive decline.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Aging
Zip Code
Cheng, Yi-Lin; Park, Jong-Sung; Manzanero, Silvia et al. (2014) Evidence that collaboration between HIF-1* and Notch-1 promotes neuronal cell death in ischemic stroke. Neurobiol Dis 62:286-95
Okun, Eitan; Griffioen, Kathleen J; Rothman, Sarah et al. (2014) Toll-like receptors 2 and 4 modulate autonomic control of heart rate and energy metabolism. Brain Behav Immun 36:90-100
Lee, Jun Ho; Patel, Kalpesh; Tae, Hyun Jin et al. (2014) Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways. FEBS Lett 588:4708-19
Lee, Jun-Ho; Halperin-Sheinfeld, Meital; Baatar, Dolgar et al. (2014) Tellurium compound AS101 ameliorates experimental autoimmune encephalomyelitis by VLA-4 inhibition and suppression of monocyte and T cell infiltration into the CNS. Neuromolecular Med 16:292-307
Longo, Valter D; Mattson, Mark P (2014) Fasting: molecular mechanisms and clinical applications. Cell Metab 19:181-92
Jo, Dong-Gyu; Arumugam, Thiruma V; Woo, Ha-Na et al. (2010) Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer's disease. Neurobiol Aging 31:917-25
Okun, Eitan; Griffioen, Kathleen J; Lathia, Justin D et al. (2009) Toll-like receptors in neurodegeneration. Brain Res Rev 59:278-92
Arumugam, T V; Woodruff, T M; Lathia, J D et al. (2009) Neuroprotection in stroke by complement inhibition and immunoglobulin therapy. Neuroscience 158:1074-89
Wheeler, David; Knapp, Edward; Bandaru, Veera V R et al. (2009) Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors. J Neurochem 109:1237-49
Liu, Manchang; Liang, Yideng; Chigurupati, Srinivasulu et al. (2008) Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol 19:1360-70

Showing the most recent 10 out of 15 publications