A neural cell adhesion molecule-derived peptide, FGL, attenuates glial cell activation in the aged hippocampus

Ojo, Bunmi; Rezaie, Payam; Gabbott, P.L.A.; Cowely, Thelma R.; Medvedev, Nikolay; Lynch, Marina A.; Stewart, Michael G.

doi:10.1016/j.expneurol.2011.09.025

Cited by 26 publications

(23 citation statements)

References 86 publications

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“…The volume of the right hippocampus as guided by bregma co-ordinates (−0.94 to −3.28 mm) and the corpus callosum (bound by bregma co-ordinates −0.94 to −2.30 mm) was determined by quantitative light microscopy using the Cavalieri method as described elsewhere (Ojo et al, 2011). In brief, rostrocaudal sections from the extent of the right hippocampus of each animal (taking every sixth serial section) were mounted onto superfrost plus slides, after washing with 0.1 M PB at pH 7.4 to remove the cryoprotectant storage solution.…”

Section: Methodsmentioning

confidence: 99%

Neurobehavioral, neuropathological and biochemical profiles in a novel mouse model of co-morbid post-traumatic stress disorder and mild traumatic brain injury

Ojo

Greenberg

Leary

et al. 2014

Front. Behav. Neurosci.

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Co-morbid mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) has become the signature disorder for returning combat veterans. The clinical heterogeneity and overlapping symptomatology of mTBI and PTSD underscore the need to develop a preclinical model that will enable the characterization of unique and overlapping features and allow discrimination between both disorders. This study details the development and implementation of a novel experimental paradigm for PTSD and combined PTSD-mTBI. The PTSD paradigm involved exposure to a danger-related predator odor under repeated restraint over a 21 day period and a physical trauma (inescapable footshock). We administered this paradigm alone, or in combination with a previously established mTBI model. We report outcomes of behavioral, pathological and biochemical profiles at an acute timepoint. PTSD animals demonstrated recall of traumatic memories, anxiety and an impaired social behavior. In both mTBI and combination groups there was a pattern of disinhibitory like behavior. mTBI abrogated both contextual fear and impairments in social behavior seen in PTSD animals. No major impairment in spatial memory was observed in any group. Examination of neuroendocrine and neuroimmune responses in plasma revealed a trend toward increase in corticosterone in PTSD and combination groups, and an apparent increase in Th1 and Th17 proinflammatory cytokine(s) in the PTSD only and mTBI only groups respectively. In the brain there were no gross neuropathological changes in any groups. We observed that mTBI on a background of repeated trauma exposure resulted in an augmentation of axonal injury and inflammatory markers, neurofilament L and ICAM-1 respectively. Our observations thus far suggest that this novel stress-trauma-related paradigm may be a useful model for investigating further the overlapping and distinct spatio-temporal and behavioral/biochemical relationship between mTBI and PTSD experienced by combat veterans.

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Section: Methodsmentioning

confidence: 99%

Neurobehavioral, neuropathological and biochemical profiles in a novel mouse model of co-morbid post-traumatic stress disorder and mild traumatic brain injury

Ojo

Greenberg

Leary

et al. 2014

Front. Behav. Neurosci.

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“…This suggests that the neuroprotective effects of FGL in aged animals may be dependent on glial activation status and its effects on synaptic viability, which are altered in aged animals [82]. In line with this idea, subcutaneous FGL injection reduced microglial CD11b and MHCII immunoreactivity, as well as MHC-II-positive microglial cell density in the hippocampi of aged (22 months) but not young rats [83]. Of note, FGL treatment actually enhanced MHC-II-ir in the dentate gyrus/hilus region of young rats, although the explanation for this opposite effect is unclear.…”

Section: Fgf2 and Neurodegeneration: Therapeutic Innovationsmentioning

confidence: 95%

Fibroblast Growth Factor-2 Signaling in Neurogenesis and Neurodegeneration

Woodbury

Ikezu

2013

J Neuroimmune Pharmacol

208

156

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Fibroblast growth factor-2 (FGF2), also known as basic FGF, is a multi-functional growth factor. One of the 22-member FGF family, it signals through receptor tyrosine kinases encoding FGFR1-4. FGF2 activates FGFRs in cooperation with heparin or heparin sulfate proteoglycan to induce its pleiotropic effects in different tissues and organs, which include potent angiogenic effects and important roles in the differentiation and function of the central nervous system (CNS). FGF2 is crucial to development of the CNS, which explains its importance in adult neurogenesis. During development, high levels of FGF2 are detected from neurulation onwards. Moreover, developmental expression of FGF2 and its receptors is temporally and spatially regulated, concurring with development of specific brain regions including the hippocampus and substantia nigra pars compacta. In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. FGFR1 signaling also modulates inflammatory signaling through the surface glycoprotein CD200, which regulates microglial activation. Because of its importance in adult neurogenesis and neuroinflammation, manipulation of FGF2/FGFR1 signaling has been a focus of therapeutic development for neurodegenerative disorders, such as Alzheimer’s disease, multiple sclerosis, Parkinson’s disease and traumatic brain injury. Novel strategies include intranasal administration of FGF2, administration of an NCAM-derived FGFR1 agonist, and chitosan-based nanoparticles for the delivery of FGF2 in pre-clinical animal models. In this review, we highlight current research towards therapeutic interventions targeting FGF2/FGFR1 in neurodegenerative disorders.

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“…Several studies have also reported reduced levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the aging rodent hippocampus and medial PFC (Fox et al 1995;Seki and Arai 1995;Abrous et al 1997;Seki 2002;Varea et al 2009), further suggesting the potential role of NCAM alterations in the reduced structural and functional plasticity observed in the aging brain. Strikingly, systemic treatment of aged rats with the NCAM-derived peptide FGL (FG-loop, synthetic NCAM mimetic peptide for the activation of FGFRs), which mimics the NCAM interactions with FGFR1 and facilitates AMPA receptor synaptic delivery (Knafo et al 2012) to improve memory formation (Cambon et al 2004), exerts neuroprotective effects in a number of aging-associated cellular and molecular alterations (Popov et al 2008;Ojo et al 2011Ojo et al , 2012.…”

mentioning

confidence: 99%

Age-related cognitive impairments in mice with a conditional ablation of the neural cell adhesion molecule

et al. 2013

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Most of the mechanisms involved in neural plasticity support cognition, and aging has a considerable effect on some of these processes. The neural cell adhesion molecule (NCAM) of the immunoglobulin superfamily plays a pivotal role in structural and functional plasticity and is required to modulate cognitive and emotional behaviors. However, whether aging is associated with NCAM alterations that might contribute to age-related cognitive decline is not currently known. In this study, we determined whether conditional NCAM-deficient mice display increased vulnerability to age-related cognitive and emotional alterations. We assessed the NCAM expression levels in the hippocampus and medial prefrontal cortex (mPFC) and characterized the performance of adult and aged conditional NCAM-deficient mice and their age-matched wild-type littermates in a delayed matching-to-place test in the Morris water maze and a delayed reinforced alternation test in the T-maze. Although aging in wild-type mice is associated with an isoform-specific reduction of NCAM expression levels in the hippocampus and mPFC, these mice exhibited only mild impairments in working/episodic-like memory performance. However, aged conditional NCAM-deficient mice displayed pronounced impairments in both the delayed matching-to-place and the delayed reinforced alternation tests. Importantly, the deficits of aged NCAM-deficient mice in these working/episodic-like memory tasks could not be attributed to increased anxiety-like behaviors or to differences in locomotor activity. Taken together, these data indicate that reduced NCAM expression in the forebrain might be a critical factor for the occurrence of cognitive impairments during aging.[Supplemental material is available for this article.]One of the hallmarks of normal aging is a gradual decline in cognitive function associated with the progressive reduction of structural and functional plasticity in brain regions that play a key role in cognitive functions, such as the hippocampus and the prefrontal cortex (Seki and

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A neural cell adhesion molecule-derived peptide, FGL, attenuates glial cell activation in the aged hippocampus

Cited by 26 publications

References 86 publications

Neurobehavioral, neuropathological and biochemical profiles in a novel mouse model of co-morbid post-traumatic stress disorder and mild traumatic brain injury

Neurobehavioral, neuropathological and biochemical profiles in a novel mouse model of co-morbid post-traumatic stress disorder and mild traumatic brain injury

Fibroblast Growth Factor-2 Signaling in Neurogenesis and Neurodegeneration

Age-related cognitive impairments in mice with a conditional ablation of the neural cell adhesion molecule

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