Hypocretinergic and cholinergic contributions to sleep-wake disturbances in a mouse model of traumatic brain injury.

Disorders of sleep and wakefulness occur in the majority of individuals who have experienced traumatic brain injury (TBI), with increased sleep need and excessive daytime sleepiness often reported. Behavioral and pharmacological therapies have limited efficacy, in part, because the etiology of post-TBI sleep disturbances is not well understood. Severity of injuries resulting from head trauma in humans is highly variable, and as a consequence so are their sequelae.

Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury.

Background: Neuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI). Microglia are highly plastic cells with dual roles in neuronal injury and recovery. Recent studies suggest that the chemokine fractalkine (CX3CL1, FKN) mediates neural/microglial interactions via its sole receptor CX3CR1.

The role of microglia in adult hippocampal neurogenesis.

Our view of microglia has dramatically changed in the last decade. From cells being "silent" in the healthy brain, microglia have emerged to be actively involved in several brain physiological functions including adult hippocampal neurogenesis, and cognitive and behavioral function. In light of recent discoveries revealing a role of microglia as important effectors of neuronal circuit reorganization, considerable attention has been focused on how microglia and hippocampal neurogenesis could be an interdependent phenomenon.

Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy.

Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, glial activation, and neurodegeneration. In mouse models, inflammatory activation of microglia accelerates tau pathology. The chemokine fractalkine serves as an endogenous neuronal modulator to quell microglial activation.

A single administration of human umbilical cord blood T cells produces long-lasting effects in the aging hippocampus.

Neurogenesis occurs throughout life but significantly decreases with age. Human umbilical cord blood mononuclear cells (HUCB MNCs) have been shown to increase the proliferation of neural stem cells (NSCs) in the dentate gyrus (DG) of the hippocampus and the subgranular zone of aging rats (Bachstetter et al., BMC Neurosci 9:22, 2008), but it is unclear which fraction or combination of the HUCB MNCs are responsible for neurogenesis.

The soluble isoform of CX3CL1 is necessary for neuroprotection in a mouse model of Parkinson's disease.

The chemokine CX3CL1/fractalkine is expressed by neurons as a transmembrane-anchored protein that can be cleaved to yield a soluble isoform. However, the roles for these two types of endogenous CX3CL1 in neurodegenerative pathophysiology remain elusive. As such, it has been difficult to delineate the function of the two isoforms of CX3CL1, as both are natively present in the brain.

CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity.

The protective/neurotoxic role of fractalkine (CX3CL1) and its receptor CX3C chemokine receptor 1 (CX3CR1) signaling in neurodegenerative disease is an intricate and highly debated research topic and it is becoming even more complicated as new studies reveal discordant results. It appears that the CX3CL1/CX3CR1 axis plays a direct role in neurodegeneration and/or neuroprotection depending on the CNS insult. However, all the above studies focused on the role of CX3CL1/CX3CR1 signaling in pathological conditions, ignoring the relevance of CX3CL1/CX3CR1 signaling under physiological conditions.

Neuron-Microglia Dialogue and Hippocampal Neurogenesis in the Aged Brain.

Age-related changes in innate immune function and glial-neuronal communication are early and critical events in brain aging and neurodegenerative disease, and lead to a chronic increase in oxidative stress and inflammation, which initiates neuronal dysfunction and reduced synaptic plasticity, and ultimately disruption in learning and memory in the aged brain. Several lines of evidence suggest a correlation between adult neurogenesis and learning. It has been proposed that a decline in hippocampal neurogenesis contributes to a physiologic decline in brain function.

Role of TNFα Induced Inflammation in Delay Eyeblink Conditioning in Young and Aged Rats.

Tumor necrosis factor alpha (TNF-α) is a multifunctional proinflammatory cytokine, which is a critical inflammatory mediator involved in aging and neurodegenerative diseases of aging. Previous work has shown that diets enriched with antioxidants reduce levels of the cytokine TNF-α and improve classical eyeblink conditioning performance. Therefore we tested the hypothesis that the proinflamatory cytokine TNF-α may be a critical factor that modulates classical conditioning behavior.

Neuroimmunomodulation and Aging.

Inflammation is by definition a protective phase of the immune response. The very first goal of inflammation is destroying and phagocytosing infected or damaged cells to avoid the spread of the pathogen or of the damage to neighboring, healthy, cells. However, we now know that during many chronic neurological disorders, inflammation and degeneration always coexist at certain time points.

CD45 deficiency drives amyloid-β peptide oligomers and neuronal loss in Alzheimer's disease mice.

Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-β peptide (Aβ) but deficient in CD45 (PSAPP/CD45(-/-) mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Aβ, decreased plasma soluble Aβ, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-α and interleukin-1β, and neuronal loss in PSAPP/CD45(-/-) mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes).

CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease.

Background: Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of the neurodegeneration is unknown. Neuroinflammation has been clearly shown in Parkinson's disease and may be involved in the progressive nature of the disease.

NT-020, a natural therapeutic approach to optimize spatial memory performance and increase neural progenitor cell proliferation and decrease inflammation in the aged rat.

The process of aging is linked to oxidative stress, microglial activation, and proinflammatory factors, which are known to decrease cell proliferation and limit neuroplasticity. These factors may lead the transition from normal aging to more severe cognitive dysfunction associated with neurodegenerative diseases. We have shown that natural compounds such as polyphenols from blueberry and green tea and amino acids like carnosine are high in antioxidant and antiinflammatory activity that decreases the damaging effects of reactive oxygen species (ROS), in the blood, brain, and other tissues of the body.

Spirulina promotes stem cell genesis and protects against LPS induced declines in neural stem cell proliferation.

Adult stem cells are present in many tissues including, skin, muscle, adipose, bone marrow, and in the brain. Neuroinflammation has been shown to be a potent negative regulator of stem cell and progenitor cell proliferation in the neurogenic regions of the brain. Recently we demonstrated that decreasing a key neuroinflammatory cytokine IL-1beta in the hippocampus of aged rats reversed the age-related cognitive decline and increased neurogenesis in the age rats.

Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats.

Microglia have neuroprotective capacities, yet chronic activation can promote neurotoxic inflammation. Neuronal fractalkine (FKN), acting on CX(3)CR1, has been shown to suppress excessive microglia activation. We found that disruption in FKN/CX(3)CR1 signaling in young adult rodents decreased survival and proliferation of neural progenitor cells through IL-1β.

Increased neuronal proliferation in the dentate gyrus of aged rats following neural stem cell implantation.

It is now well accepted that the brain is able to generate newborn neurons from a population of resident multipotential neural stem cells (NSCs) located in two discrete regions of the brain. The capacity for neurogenesis appears to diminish over the lifespan of an organism. Methods to potentiate the proliferation of new neuronal or glial cells within the central nervous system from resident NSCs could have therapeutic potential following an insult, such as stroke, or to replace lost cells as a result of a neurodegenerative disease.

Human umbilical cord blood treatment in a mouse model of ALS: optimization of cell dose.

Background: Amyotrophic Lateral Sclerosis (ALS) is a multicausal disease characterized by motor neuron degeneration in the spinal cord and brain. Cell therapy may be a promising new treatment for this devastating disorder. We recently showed that a single low dose (10(6) cells) of mononuclear human umbilical cord blood (MNC hUCB) cells administered intravenously to G93A mice delayed symptom progression and modestly prolonged lifespan.

Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain.

Background: Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation.

Results: We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells.

Blockade of caspase-1 increases neurogenesis in the aged hippocampus.

Adult hippocampal neurogenesis dramatically decreases with increasing age, and it has been proposed that this decline contributes to age-related memory deficits. Central inflammation contributes significantly to the decrease in neurogenesis associated with ageing. Interleukin-1beta is a proinflammatory cytokine initially synthesized as an inactive precursor that is cleaved by caspase-1 to generate the biologically active mature form.

Interleukin-1beta and caspase-1: players in the regulation of age-related cognitive dysfunction.

Scientific research on the unprecedented and growing number of older adults in the United States and other industrialized countries has focused much attention on the health consequences of aging. Over the last few decades, inflammation in the brain and its implication in the progression of aging and age-related cognitive dysfunction has been an area of increasing importance to neuroscientists and is now considered as one of the most interesting and promising topics for aging research. One of the critical aspects of inflammatory processes is that the activation of one upstream inflammatory molecule initiates a cascade of self-sustaining inflammatory events which leads to the activation of a number of different downstream functions.

Early inhibition of TNFalpha increases 6-hydroxydopamine-induced striatal degeneration.

Evidence suggests that tumor necrosis factor alpha (TNF) is a leading cause of dopaminergic neuronal cell death. TNF also, however, has neuroprotective effects. Thus, TNF might have a dual role following injury: immediate release after injury is protective, whereas chronic increases are detrimental.

Novel cell therapy approaches for brain repair.

Numerous reports elucidate that tissue-specific stem cells are phenotypically plastic and their differentiation pathways are not strictly delineated. Although the identity of all the epigenetic factors which may trigger stem cells to make a lineage selection are still unknown, the plasticity of adult stem cells opens new approaches for their application in the treatment of various disorders. There is increasing researcher interest in hematopoietic stem cells for treatment of not only blood-related diseases but also various unrelated disorders including neurodegenerative diseases.

Cord blood rescues stroke-induced changes in splenocyte phenotype and function.

The neuroprotective mechanism of human umbilical cord blood cells (HUCBC) in the rat middle cerebral artery occlusion (MCAO) stroke model remains uncertain. Given the inflammatory sequelae that occur following stroke, we investigated whether HUCBC protection could be derived from the modulation of this immuno-inflammatory event, suggested by the attraction of the HUCBC to the spleen. We found that, following MCAO, rat spleen size was reduced concomitantly with their CD8+ T-cell counts.

Anti-inflammatory effects of human cord blood cells in a rat model of stroke.

When human umbilical cord blood cells (HUCBCs) are administered intravenously after a middle cerebral artery occlusion, they reliably produce behavioral and anatomical recovery, and protect neural tissue from progressive change. However, our results indicate that the cells do not exert their effects by engraftment in the peri-infarct region, even though they migrate to the site of injury. The objective of the present study was to determine if the cells induce recovery by decreasing inflammation.