Journal of Neurodegeneration and RegenerationAbstracts
Journal of Neurodegeneration and Regeneration ®

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Journal of Neurodegeneration and Regeneration
Fall 2009, Volume 2
, Number 1


Article
Editorial Adult neurogenesis in the pathogenesis of Alzheimer’s disease
Philippe Taupin, PhD, Editor-in-Chief–Research
Fall 2009; pages 6-8


Article
Characterization and isolation of synapses of newly generated neuronal cells of the adult hippocampus at early stages of neurogenesis
Philippe Taupin, PhD
Fall 2009; pages 9-17

Abstract
Neurogenesis continues throughout adulthood in the mammalian brain. Over the past decade, significant progresses have been made in the field of adult neurogenesis and neural stem cell research, but the synapses of newly generated neuronal cells of the adult brain remain unidentified and uncharacterized, particularly at the early stages of neurogenesis. We studied adult neurogenesis neosynaptogenesis by immunohistology and electron microscopy, in the hippocampus of transgenic mice expressing enhanced green fluorescent protein (EGFP) under the nestin enhancer. Newly generated neuronal cells of the adult dentate gyrus (DG) express nestin, during their first week of development. Hence, we studied the early stages of adult neurogenesis neosynaptogenesis. Newly generated neuronal cells of the adult DG, expressing GFP, establish synaptic contacts in the region of the stratum lucidum. These synapses elicit morphological features of synapses of immature granule cells; a large size, a relatively low density of synaptic vesicles and immature postsynaptic densities (PSDs). Synapses of newly generated neuronal cells expressing GFP were isolated and purified by fluorescence activated cell sorting (FACS), as synaptosomes, and characterized by electron microscopy. This study confirms the phenotype of newly generated neuronal cells of the adult DG, as granule-like cells, and provides a preparation to study the physiology and pharmacology of adult neurogenesis. Key words: Neurogenesis, Neural stem cells, Granule cells, Mossy fibers, Synaptogenesis, Synaptosomes


Article
A chondroitinase-treated, decellularized nerve allograft compares favorably to the cellular isograft in rat peripheral nerve repair
James B. Graham, BA; Qing-Shan Xue, PhD; Debbie Neubauer, MS; David Muir, PhD
Fall 2009; pages 19-29

Abstract
Objective: There is a pressing need for an effective and practical alternative to nerve autografting. Detergent extraction is an effective means to decellularize nerve grafts, thereby eliminating immunogenic proteins and primary concerns of allogenic immunorejection. In addition, chondroitin sulfate proteoglycan (CSPG) that inhibits axonal growth persists after detergent extraction, indicating that decellularized nerve grafts can be optimized further by extracting inhibitory CSPG. Design: This study evaluated a nerve graft that was decellularized with detergents, treated with chondroitinase ABC to degrade inhibitory CSPG, and irradiated for sterility (DCI-graft). DCI-grafts were prepared by a proprietary processing method and provided by AxoGen (Alachua, FL). The DCI-graft was tested as an allogenic transplant and was compared with cellular nerve isografts in rats. Main Outcome Measures: Recovery of motor and sensory functions was assessed biweekly for 24 weeks after nerve graft repair followed by digital axon morphometry. Results: Both DCI-grafts and isografts were well tolerated and supported robust nerve regeneration. The numbers of regenerated axons in recipient nerves distal to the grafts were not statistically different in the two graft conditions. Overall, the time course and extent of recovery in four function tests were similar or improved with the DCI-graft compared with the isograft. In particular, the DCI-graft group showed a significant improvement in the recovery of thermal pain. Conclusions: A nerve graft process was developed that removes immunogenic cellular material and inhibitory CSPG while preserving the nerve sheath structure and growth-promoting properties that support regeneration. The processed nerve allografts compare favorably to nerve isografts in the support of axonal regeneration and recovery of function. These results indicate that decellularized, chondroitinasetreated nerve grafts may provide an operative alternative to nerve autografting. Key words: Decellularized nerve graft, Autograft, Chondroitinase, Nerve regeneration, Recovery of function, Axon morphometry


Article
Isoform-specific effects of apolipoprotein E on microglial activation in cortical and microglial cultures from adult mouse brain
Anna G. Barsukova, MS; Robert G. Struble, PhD; Britto P. Nathan, PhD
Fall 2009; pages 31-38

Abstract
The apolipoprotein E (apoE) genotype is a prognostic indicator for many chronic neurological diseases including Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, and recovery from head trauma. Activated microglia are a common pathological feature of many neurological conditions. Therefore, the authors examined the effects of apoE isoforms on microglial proliferation, morphology, and activation in mixed cortical and in microglial-enriched cultures from adult mice. Mixed cortical and microglial-enriched cultures from adult apoE gene deficient/knockout (KO) mice were grown in medium alone or in medium containing purified recombinant human apoE3 or human apoE4 (3 µg/mL). Following stimulation with lipopolysaccharide (LPS), microglial density and morphology were evaluated by immunocytochemistry. Levels of inducible nitric oxide synthase (iNOS) were quantified by immunoblotting. The results revealed that apoE3 significantly decreased both the number of activated microglia and iNOS production more so than did apoE4 which, in turn, was better than media alone. Furthermore, these isoform specific effects were more pronounced in the mixed culture than in the pure microglial culture. Thus, apoE affects microglial activation and this effect is amplified by the concurrent presence of astroglia and neurons. These data suggest a potential mechanism whereby apoE genotype may play a complex role in numerous chronic neurological conditions. Key words: Microglia, Alzheimer’s disease, Apolipoprotein E, Glial activation, iNOS


Article
Effects of facial nerve axotomy on Th2-associated and Th1-associated chemokine mRNA expression in the facial motor nucleus of wild-type and presymptomatic SOD1 mice
Derek A. Wainwright, PhD; Nichole A. Mesnard, BS; Junping Xin, MD, PhD; Virginia M. Sanders, PhD; Kathryn J. Jones, PhD
Fall 2009; pages 39-44

Abstract
The authors have previously demonstrated a neuroprotective mechanism of facial motoneuron (FMN) survival after facial nerve transection that is dependent on CD4+T helper 2 (Th2) cell interactions with peripheral antigen presenting cells, as well as central nervous system (CNS) resident microglia. Pituitary adenylyl cyclase activating polypeptide is expressed by injured FMN and increases Th2-associated chemokine expression in cultured murine microglia. Collectively, these data suggest a model involving CD4+ Th2 cell migration to the facial motor nucleus after injury via microglial expression of Th2-associated chemokines. In this study, the authors tested the hypothesis that Th2-associated chemokine expression occurs in the facial motor nucleus after facial nerve axotomy at the stylomastoid foramen. Initial microarray analysis of Th2-associated and Th1-associated chemokine mRNA levels was accomplished after facial nerve axotomy in wild type (WT) and presymptomatic mutant superoxide dismutase 1 (mSOD1) [model of familial amyotrophic lateral sclerosis (ALS)] mice. Based on that initial microarray analysis, the Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, were further analyzed by RT-PCR. The results indicate that facial nerve injury predominantly increases Th2-associated chemokine, but not Th1-associated chemokine mRNA levels in the mouse facial motor nucleus. Interestingly, no differences were detected between WT and mSOD1 mice for CCL11 and CXCL11 after injury. These data provide a basis for further investigation into Th2-associated chemokine expression in the facial motor nucleus after FMN injury, which may lead to more specifically targeted therapeutics in motoneuron diseases, such as ALS. Key words: CCL11, CXCL11, Neuroprotection, Chemokine


Article
Can vision be restored following a human optic nerve lesion?
Damien P. Kuffler, PhD
Fall 2009; pages 45-63

Abstract
Most forms of eye trauma, including brunt and penetrating insults, tumors, or glaucoma lead to irreversible and permanent damage to retinal ganglion cells (RGCs) and their axons resulting in blindness. The annual incidence of blindness in the United States is one in 28 for persons more than 40 years of age, and is approaching 1.6 million persons. Blindness is permanent because when RGC axons are damaged, the RGCs die, and once killed, they are not replaced, and that injured RGC axons cannot regenerate. The failure of RGC axons to regenerate is because the cellular environment of the adult mammalian central nervous system (CNS) inhibits rather than promotes axon regeneration. To restore vision, it requires maintaining the viability of axotomized RGCs, preventing inhibition of axon regeneration, and providing factors that promote axon regeneration along the optic nerve, and into the CNS, where they must reestablish their appropriate retinotopic synaptic connections. In adult mammalian models, axotomized RGCs can be maintained viable, their axons can be induced to regenerate, and functional synaptic connections form in the brain, giving rise to perceptions of light and dark. However, true reestablishment of vision has never been achieved. This review examines both trauma and disease causes of blindness and standard techniques used to optimize the possibility of reestablishing vision following trauma to the eye and the optic nerve by preventing RGC death and promoting axon regeneration. New techniques are also considered that may be used in conjunction with current techniques to reestablish vision following optic nerve trauma. Key words: Optic nerve, RGC, Axon regeneration, Glial scar, Neurotrophic factors, Activated astrocytes