Age-related changes in the hippocampus (loss of synaptophysin and glial–synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL

Ojo, Bunmi; Rezaie, Payam; Gabbott, P.L.A.; Davies, Heather A.; Colyer, Frances; Cowley, Thelma R.; Lynch, Marina A.; Stewart, Michael G.

doi:10.1016/j.bbi.2011.09.013

Cited by 49 publications

(37 citation statements)

References 79 publications

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“…The decrease in CD200 concurs with our previous findings (Lyons et al, 2007a) and the age-related decrease in synaptophysin in hippocampus is similar to that described previously in the dentate gyrus (Davies et al, 2003;Mullany and Lynch, 1997) and is consistent with the finding that CD200 is expressed at synapses (Ojo et al, 2011).…”

Section: Synaptophysin and Cd200 Are Decreased With Agesupporting

confidence: 82%

“…These findings confirm the previously-reported age-related decrease in CD200 (Lyons et al, 2007a) and suggest that the loss of synapses, indicated by decreased synaptophysin, might contribute to this change. Interestingly, CD200 has been reported to be expressed on presynaptic terminals where co-localization with synaptophysin has been observed (Ojo et al, 2011). There was no evidence of an agerelated change in CD200R.…”

Section: Discussionmentioning

confidence: 68%

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CD200 fusion protein decreases microglial activation in the hippocampus of aged rats

Cox

Carney

Miller

et al. 2012

Brain, Behavior, and Immunity

100

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Please cite this article as: Fionnuala Cox, F., Carney, D., Miller, A-M., Lynch, M.A., CD200 fusion protein decreases microglial activation in the hippocampus of aged rats, Brain, Behavior, and Immunity (2011), doi: 10.1016/j.bbi. 2011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe glycoprotein, CD200, is primarily expressed on neurons and its cognate receptor CD200R is expressed principally on cells of the myeloid lineage, including microglia. The interaction of CD200 with its receptor plays a significant role in maintaining microglia in a quiescent state and therefore a decrease in CD200 expression in brain is associated with evidence of microglial activation. Conversely, activation of CD200R, for example using a CD200 fusion protein (CD200Fc), should result in a decrease in microglial activation. Here we assessed the effect of delivery of CD200Fc intrahippocampally on microglial activation and on long-term potentiation (LTP) in perforant path-granule cell synapses in young and aged rats. We hypothesized that the age-related changes in microglial activation would be attenuated by CD200Fc resulting in an improved ability of aged rats to sustain LTP. The data indicate that expression of markers of microglial activation including major histocompatibility complex Class II (MHCII) and CD40 mRNA, as well as MHCII immunoreactivity, were increased in hippocampus of aged, compared with young, rats and that these changes were associated with a deficit in LTP; these changes were attenuated in hippocampal tissue prepared from aged rats which received CD200Fc. Microglial activation and a deficit in LTP have also been reported in lipopolysaccharide (LPS)-treated rats and, here, we report that these changes were also attenuated in CD200Fc-treated animals. Thus the negative impact of microglial activation on the ability of aged and LPS-treated rats to sustain LTP is ameliorated when CD200R is activated by CD200Fc.

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Section: Synaptophysin and Cd200 Are Decreased With Agesupporting

confidence: 82%

Section: Discussionmentioning

confidence: 68%

CD200 fusion protein decreases microglial activation in the hippocampus of aged rats

Cox

Carney

Miller

et al. 2012

Brain, Behavior, and Immunity

100

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“…16 FGL proved to exert beneficial effects in different models of neurological or psychiatric diseases. 6,7,[11][12][13][14]20 In the present study, repeated administration of the peptide mimetic FGL affected kindling progression as well as associated alterations in the number of neuronal progenitor cells and early postmitotic cells. The impact of FGL on kindling progression is indicated by a reduced number of stimulations necessary to induce a generalized seizure.…”

Section: ■ Results and Discussionmentioning

confidence: 89%

“…6,13,14 Pharmacokinetic studies have confirmed a relevant brain penetration rate of the peptide in rats and humans. FGL concentrations proved to be detectable in the cerebrospinal fluid of rats within 10 min following subcutaneous administration resulting in stable concentrations up to 5 h. 19 In humans, concentrations in the cerebrospinal fluid have been analyzed following intranasal administration, thus confirming relevant brain access in translational studies.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Impact of the Neural Cell Adhesion Molecule-Derived Peptide FGL on Seizure Progression and Cellular Alterations in the Mouse Kindling Model

Zellinger

Salvamoser

Seeger

et al. 2014

ACS Chem. Neurosci.

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The neural cell adhesion molecule peptide mimetic fibroblast growth loop (FGL) proved to exert neuroprotective, neurotrophic, and anti-inflammatory effects in different in vitro and in vivo experiments. Based on this beneficial efficacy profile, it is currently in clinical development for neurodegenerative diseases and brain insults. Here, we addressed the hypothesis that the peptide might affect development of seizures in a kindling paradigm, as well as associated behavioral and cellular alterations. Both doses tested, 2 and 10 mg/kg FGL, significantly reduced the number of stimulations necessary to induce a generalized seizure. FGL did not exert relevant effects on the behavioral patterns of kindled animals. As expected, kindling increased the hippocampal cell proliferation rate. Whereas the low dose of FGL did not affect this kindling-associated alteration, 10 mg/kg FGL proved to attenuate the expansion of the doublecortin-positive cell population. These data suggest that FGL administration might have an impact on disease-associated alterations in the hippocampal neuronal progenitor cell population. In conclusion, the effects of the peptide mimetic FGL in the kindling model do not confirm a disease-modifying effect with a beneficial impact on the development or course of epilepsy. The results obtained with FGL rather raise some concern regarding a putative effect, which might promote the formation of a hyperexcitable network. Future studies are required to further assess the risks in models with development of spontaneous seizures.

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“…Even during oestrus cycle there is an intense fluctuation in dendritic density in rodents. Furthermore, ovariectomy or menopause itself results in a significant decrease of synaptic and dendritic density (Ojo et al, 2011;Woolley and McEwen, 1992). Data on estrogen effect also suggest that it acts directly at synapses by activating second messenger signaling, resulting in a rapid altering in neuronal excitability, synaptic transmission, and/or synaptic plasticity (Woolley, 2007).…”

Section: Estrogen: Afforded Protection and Plasticity Following Brainmentioning

confidence: 99%

Brain Plasticity Following Ischemia: Effect of Estrogen and Other Cerebroprotective Drugs

Wappler¹,

Felszeghy²,

Varshney³

et al. 2012

Advances in the Treatment of Ischemic Stroke

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Age-related changes in the hippocampus (loss of synaptophysin and glial–synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL

Cited by 49 publications

References 79 publications

CD200 fusion protein decreases microglial activation in the hippocampus of aged rats

CD200 fusion protein decreases microglial activation in the hippocampus of aged rats

Impact of the Neural Cell Adhesion Molecule-Derived Peptide FGL on Seizure Progression and Cellular Alterations in the Mouse Kindling Model

Brain Plasticity Following Ischemia: Effect of Estrogen and Other Cerebroprotective Drugs

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