Carmelina Gemma

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. No approach to date has been taken to decipher the significance of defects in CX3CL1/CX3CR1 signaling in physiological condition. In the present study we used CX3CR1−/−, CX3CR1+/−, and wild-type mice to investigate the physiological role of CX3CR1 receptor in cognition and synaptic plasticity. Our results demonstrate for the first time that mice lacking the CX3CR1 receptor show contextual fear conditioning and Morris water maze deficits. CX3CR1 deficiency also affects motor learning. Importantly, mice lacking the receptor have a significant impairment in long-term potentiation (LTP). Infusion with IL-1β receptor antagonist significantly reversed the deficit in cognitive function and impairment in LTP. Our results reveal that under physiological conditions, disruption in CX3CL1 signaling will lead to impairment in cognitive function and synaptic plasticity via increased action of IL-1β.

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. Interestingly, MCAO-induced spleen size reduction correlated with the extent of ischemic damage, however, HUCBC treatment rescued the spleen weight, splenic CD8+ T-cell counts, as well as the amount of brain injury. Additionally, splenocyte proliferation assays demonstrated that HUCBC treatment opposed MCAO-associated T-cell proliferation by increasing the production of IL-10 while decreasing IFN-gamma. Taken together, these results suggest a novel immunomodulatory mechanism by which HUCBC mediate protection in the rat MCAO model of stroke.

Fractalkine and CX3CR1 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. Aged rats were found to have decreased levels of hippocampal FKN protein; moreover, interruption of CX(3)CR1 function in these animals did not affect neurogenesis. The age-related loss of FKN could be restored by exogenous FKN reversing the age-related decrease in hippocampal neurogenesis. There were no measureable changes in young animals by the addition of exogenous FKN. The results suggest that FKN/CX(3)CR1 signaling has a regulatory role in modulating hippocampal neurogenesis via mechanisms that involve indirect modification of the niche environment. As elevated neuroinflammation is associated with many age-related neurodegenerative diseases, enhancing FKN/CX(3)CR1 interactions could provide an alternative therapeutic approach to slow age-related neurodegeneration.

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

BackgroundParkinsons 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 Parkinsons disease and may be involved in the progressive nature of the disease. Microglia are capable of producing neuronal damage through the production of bioactive molecules such as cytokines, as well as reactive oxygen species (ROS), and nitric oxide (NO). The inflammatory response in the brain is tightly regulated at multiple levels. One form of immune regulation occurs via neurons. Fractalkine (CX3CL1), produced by neurons, suppresses the activation of microglia. CX3CL1 is constitutively expressed. It is not known if addition of exogenous CX3CL1 beyond otherwise physiologically normal levels could decrease microglia activation and thereby minimize the secondary neurodegeration following a neurotoxic insult.MethodsThe intrastriatal 6-hydroxydopamine (6-OHDA) rat model of Parkinson disease, was used to test the hypothesis that exogenous CX3CL1 could be neuroprotective. Treatment with recombinant CX3CL1 was delivered to the striatum by an osmotic minipump for 28 days beginning 7 days after the initial insult. Unbiased stereological methods were used to quantify the lesion size in the striatum, the amount of neuronal loss in the substantia nigra, and the amount of microglia activation.ResultsAs hypothesized, CX3CL1 was able to suppress this microglia activation. The reduced microglia activation was found to be neuroprotective as the CX3CL1 treated rats had a smaller lesion volume in the striatum and importantly significantly fewer neurons were lost in the CX3CL1 treated rats.ConclusionThese findings demonstrated that CX3CL1 plays a neuroprotective role in 6-OHDA-induced dopaminergic lesion and it might be an effective therapeutic target for many neurodegenerative diseases, including Parkinson disease and Alzheimer disease, where inflammation plays an important role.

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 (106 cells) of mononuclear human umbilical cord blood (MNC hUCB) cells administered intravenously to G93A mice delayed symptom progression and modestly prolonged lifespan. The aim of this pre-clinical translation study is to optimize the dose of MNC hUCB cells to retard disease progression in G93A mice. Three different doses of MNC hUCB cells, 10×106, 25×106 and 50×106, were administered intravenously into pre-symptomatic G93A mice. Motor function tests and various assays to determine cell effects were performed on these mice. Methodology/Principal Findings Our results showed that a cell dose of 25×106 cells significantly increased lifespan of mice by 20–25% and delayed disease progression by 15%. The most beneficial effect on decreasing pro-inflammatory cytokines in the brain and spinal cord was found in this group of mice. Human Th2 cytokines were found in plasma of mice receiving 25×106 cells, although prevalent human Th1 cytokines were indicated in mice with 50×106 cells. High response of splenic cells to mitogen (PHA) was indicated in mice receiving 25×106 (mainly) and 10×106 cells. Significantly increased lymphocytes and decreased neutrophils in the peripheral blood were found only in animals receiving 25×106 cells. Stable reduction in microglia density in both cervical and lumbar spinal cords was also noted in mice administered with 25×106 cells. Conclusions/Significance These results demonstrate that treatment for ALS with an appropriate dose of MNC hUCB cells may provide a neuroprotective effect for motor neurons through active involvement of these cells in modulating the host immune inflammatory system response.

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

BackgroundNeurogenesis 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.ResultsWe 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. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis.ConclusionThe results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

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. In this review the role of microglia in the adult hippocampal neurogenesis under physiological condition is discussed.

Blueberry- and spirulina-enriched diets enhance striatal dopamine recovery and induce a rapid, transient microglia activation after injury of the rat nigrostriatal dopamine system

Neuroinflammation plays a critical role in loss of dopamine neurons during brain injury and in neurodegenerative diseases. Diets enriched in foods with antioxidant and anti-inflammatory actions may modulate this neuroinflammation. The model of 6-hydroxydopamine (6-OHDA) injected into the dorsal striatum of normal rats, causes a progressive loss of dopamine neurons in the ventral mesencephalon. In this study, we have investigated the inflammatory response following 6-OHDA injected into the striatum of adult rats treated with diet enriched in blueberry or spirulina. One week after the dopamine lesion, a similar size of dopamine degeneration was found in the striatum and in the globus pallidus in all lesioned animals. At 1 week, a significant increase in OX-6- (MHC class II) positive microglia was found in animals fed with blueberry- and spirulina-enriched diets in both the striatum and the globus pallidus. These OX-6-positive cells were located within the area of tyrosine hydroxylase (TH) -negativity. At 1 month after the lesion, the number of OX-6-positive cells was reduced in diet-treated animals while a significant increase beyond that observed at 1 week was now present in lesioned control animals. Dopamine recovery as revealed by TH-immunohistochemistry was significantly enhanced at 4 weeks postlesion in the striatum while in the globus pallidus the density of TH-positive nerve fibers was not different from control-fed lesioned animals. In conclusion, enhanced striatal dopamine recovery appeared in animals treated with diet enriched in antioxidants and anti-inflammatory phytochemicals and coincided with an early, transient increase in OX-6-positive microglia.

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. Recently, a great deal of attention has been given to the interplay between inflammatory and apoptotic processes and the regulation of these processes by the caspases. The caspase family of proteases can be divided into proapoptotic and pro-inflammatory members. The present review summarizes recent observations of the interactions between the inflammatory cytokine interleuldn-1 (IL-1) beta and the inflammatory/apoptotic caspase-1 and their involvement in age-related impairments in cognition. A comprehensive understanding of these mechanisms could potentially lead to the development of preventive or protective therapies that reduce or inhibit the cognitive decline associated with aging and age-related neurodegenerative disease.

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 Alzheimers 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). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-Aβ phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Aβ oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45−/− mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Aβ oligomers and validate CD45-mediated microglial clearance of oligomeric Aβ as a novel AD therapeutic target.