Biomedical subjects

A R Harvey

Publications and source records attributed to A R Harvey.

At least 19 recordsLinked to original sources

PubMed2006

AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells.

We compared the effects of intravitreal injection of bi-cistronic adeno-associated viral (AAV-2) vectors encoding enhanced green fluorescent protein (GFP) and either ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) or growth-associated protein-43 (GAP43) on adult retinal ganglion cell (RGC) survival and regeneration following (i) optic nerve (ON) crush or (ii) after ON cut and attachment of a peripheral nerve (PN). At 7 weeks after ON crush, quantification of betaIII-tubulin immunostaining revealed that, compared to AAV-GFP controls, RGC survival was not enhanced by AAV-GAP43-GFP but was increased in AAV-CNTF-GFP (mean RGCs/retina: 17 450+/-358 s.e.m.) and AAV-BDNF-GFP injected eyes (10 200+/-4064 RGCs/retina). Consistent with increased RGC viability in AAV-CNTF-GFP and AAV-BDNF-GFP injected eyes, these animals possessed many betaIII-tubulin- and GFP-positive fibres proximal to the ON crush. However, only in the AAV-CNTF-GFP group were regenerating RGC axons seen in distal ON (1135+/-367 axons/nerve, 0.5 mm post-crush), some reaching the optic chiasm. RGCs were immunoreactive for CNTF and quantitative RT-PCR revealed a substantial increase in CNTF mRNA expression in retinas transduced with AAV-CNTF-GFP. The combination of AAV-CNTF-GFP transduction of RGCs with autologous PN-ON transplantation resulted in even greater RGC survival and regeneration. At 7 weeks after PN transplantation there were 27 954 (+/-2833) surviving RGCs/retina, about 25% of the adult RGC population. Of these, 13 352 (+/-1868) RGCs/retina were retrogradely labelled after fluorogold injections into PN grafts. In summary, AAV-mediated expression of CNTF promotes long-term survival and regeneration of injured adult RGCs, effects that are substantially enhanced by combining gene and cell-based therapies/interventions.

Animals↗

PubMed2006

Adult olfactory ensheathing glia promote the long-distance growth of adult retinal ganglion cell neurites in vitro.

In vivo, transplanted adult olfactory ensheathing glia (OEG) and adult Schwann cells (SC) can support the regrowth of at least some transected axons within adult CNS neuropil. In the present study, we developed an in vitro adult rat retinal explant model to explore the influence of primary adult SC and OEG on retinal ganglion cell (RGC) neurite regrowth in the presence of glial cells endogenous to the retina. Retinal quadrants were plated RGC-side down onto aclar hats coated with either pure collagen (type 1), collagen with OEG, collagen with SCs, or collagen coated with both OEG and SCs. Regrowing retinal neurites extended onto the pure collagen substrate, largely in association with astrocytes that migrated out from the explants (mean number of neurites: 144+/-65 SEM). The additional presence of OEG (669+/-122), but not SCs (97+/-41), supported the regrowth of significantly greater numbers of RGC neurites. Furthermore, this OEG-stimulated regeneration was over significantly greater distances; >68% of neurites extended >500 microm from the explant, compared with explants plated onto SCs or collagen alone (15% and 29%, respectively). When OEG and SCs were co-cultured the number of regenerating neurites was reduced (397+/-81) compared with the pure OEG treatment. Analysis of explants on pure collagen substrates fed with media conditioned by purified OEG or SC showed no increase in neurite outgrowth compared with control treatments, suggesting that the enhanced growth in the presence of OEG is a contact-mediated effect. The observed differences between the abilities of OEG and SC to support the growth of CNS-derived fibers in the presence of astrocytes support the suggestion that OEG may be better suited for direct transplantation into CNS neuropil following injury.

Animals↗

PubMed2006

Lengthening and transfer of hamstrings for a flexion deformity of the knee in children with bilateral cerebral palsy: technique and preliminary results.

Between July 2000 and April 2004, 19 patients with bilateral spastic cerebral palsy who required an assistive device to walk had combined lengthening-transfer of the medial hamstrings as part of multilevel surgery. A standardised physical examination, measurement of the Functional Mobility Scale score and video or instrumented gait analysis were performed pre- and post-operatively. Static parameters (popliteal angle, flexion deformity of the knee) and sagittal knee kinematic parameters (knee flexion at initial contact, minimum knee flexion during stance, mean knee flexion during stance) were recorded. The mean length of follow-up was 25 months (14 to 45). Statistically significant improvements in static and dynamic outcome parameters were found, corresponding to improvements in gait and functional mobility as determined by the Functional Mobility Scale. Mild hyperextension of the knee during gait developed in two patients and was controlled by adjustment of their ankle-foot orthosis. Residual flexion deformity > 10 degrees occurred in both knees of one patient and was treated by anterior distal femoral physeal stapling. Two children also showed an improvement of one level in the Gross Motor Function Classification System.

Adolescent↗

PubMed2005

Androgens, andropause and neurodegeneration: exploring the link between steroidogenesis, androgens and Alzheimer's disease.

The relationship between menopause and cognitive decline has been the subject of intense research since a number of studies have shown that hormone replacement therapy could reduce the risk of developing Alzheimer's disease in women. In contrast, research into andropause has only recently begun. Furthermore, evidence now suggests that steroidogenesis is not restricted to the gonads and adrenals, and that the brain is capable of producing its own steroid hormones, including testosterone and estrogen. Sex hormones have been demonstrated to be of critical importance in the embryonic development of the central nervous system (CNS); however, we are only just beginning to understand the role that these hormones may play in the normal functioning and repair of the adult mammalian CNS. This review will summarize current research into the role of androgens and andropause on cognition and the possible mechanisms of action of androgens, with particular reference to Alzheimer's disease.

Alzheimer Disease↗

PubMed2005

cAMP regulates axon outgrowth and guidance during optic nerve regeneration in goldfish.

Increased cAMP improves neuronal survival and axon regeneration in mammals. Here, we assess cAMP levels and identify activated pathways in a spontaneously regenerating central nervous system. Following optic nerve crush in goldfish, almost all retinal ganglion cells (RGC) survive and regenerate retinotectal topography. Goldfish received injections of a cAMP analogue (CPT-cAMP), a protein kinase A (PKA) inhibitor (KT5720), both compounds combined, or PBS (control). RGC survival in experimental groups was unaffected at any stage. The rate of axon regeneration was accelerated by the activator and decelerated both by the inhibitor and by combined injections, suggesting a PKA-dependent pathway. In addition, errors in regenerate retinotectal topography were observed when agents were applied in vivo and RGC response to the guidance cue ephrin-A5 in vitro was altered by the inhibitor. Our results highlight that therapeutic manipulation of cAMP levels to enhance axonal regeneration in mammals must ensure that topography, and consequently function, is not disrupted.

Animals↗

PubMed2005

Retinal ganglion cell neurotrophin receptor levels and trophic requirements following target ablation in the neonatal rat.

Superior colliculus (SC) ablation in neonatal rats results in a rapid increase in retinal ganglion cell (RGC) death. This injury-induced death is reduced by exogenous brain-derived neurotrophic factor or neurotrophin-4/5 (NT-4/5), but the protective effect of these molecules is transient, delaying but not preventing neuronal loss. We sought to discover why neurotrophins only temporarily reduce RGC death after target ablation, focusing on changes in neurotrophin receptor expression and possible changes in growth factor dependency. In unlesioned rats, receptor tyrosine kinase B (trkB) immunohistochemistry revealed no change in the number of trkB positive cells in the RGC layer 24 h after intraocular NT-4/5 injection. However, after SC lesions there were significantly less immunoreactive cells and, surprisingly, even fewer immunoreactive cells in NT-4/5 injected eyes. Semi-quantitative confocal analysis of immunofluorescence intensity revealed an increase in trkB staining in the RGC layer in unlesioned rats 24 h after NT-4/5 injection, whereas in SC-lesioned animals exposed to NT-4/5 there was a significant decrease in staining. To determine whether injured neonatal RGCs can switch their trophic requirements, different doses of ciliary neurotrophic factor were given intraocularly, either alone or combined with NT-4/5. We also tested an SC-derived chondroitin sulfate proteoglycan that has been reported to promote neonatal RGC survival. None of these interventions reduced lesion-induced RGC death 24 or 36 h after SC ablation. In summary, we show that developing RGCs do not shift their trophic dependence to other survival factors following injury; rather, the application of neurotrophins causes a down-regulation of the cognate trkB receptor, presumably altering the long-term responsiveness of neonatal RGCs to exogenous neurotrophins. These data highlight the difficulty in promoting long-term neuronal survival when using one-off administration of recombinant growth factors.

Animals↗

PubMed2005

A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: a pediatric blood and marrow transplant consortium study.

Severe mucositis is a common cause of morbidity in hematopoietic stem cell transplant (HSCT) recipients. Glutamine has been shown to reduce mucositis in children receiving chemotherapy. Patients were randomized in a double-blind manner to receive glutamine or glycine at a dose of 2 g/m(2)/dose (maximum dose 4 g) twice daily until 28 days post transplant or discharge if sooner. Mucositis was graded by use of a modified Walsh scale. A total of 120 children were evaluable: 57 children received glutamine and 63 received glycine. The mean mucositis score was 3.0+/-0.3 vs 3.9+/-0.4 (P=0.07) in the glutamine and glycine groups, respectively. The glutamine group demonstrated a reduction in mean number of days of intravenous narcotics use (12.1+/-1.5 vs 19.3+/-2.8 in the glycine group, P=0.03) and total parenteral nutrition (17.3+/-1.7 vs 27.3+/-3.6 in glycine group, P=0.01). There was no statistically significant difference in toxicity between the two groups. Glutamine appears to be safe and beneficial in reducing the severity of mucositis. Strong consideration should be given to include oral glutamine supplementation as a routine part of supportive care of SCT patients.

Administration, Oral↗

PubMed2003

Expression pattern of the stem cell leukaemia gene in the CNS of the embryonic and adult mouse.

The basic helix-loop-helix (bHLH) transcription factor stem cell leukaemia (SCL) is a 'master regulator' of haematopoiesis, where SCL is pivotal in cell fate determination and differentiation. SCL has also been detected in CNS, where other members of the bHLH-family have been shown to be indispensable for neuronal development; however, no detailed expression pattern of SCL has so far been described. We have generated a map of SCL expression in the embryonic and adult mouse brain based on histochemical analysis of LacZ reporter gene expression in sequential sections of brain tissue derived from SCL-LacZ knockin mice. The expression of LacZ was confirmed to reflect SCL expression by in situ hybridisation. LacZ expression was found in a range of different diencephalic, mesencephalic and metencephalic brain nuclei in adult CNS. Co-localisation of LacZ with the neuronal marker NeuN indicated expression in post-mitotic neurons in adulthood. LacZ expression by neurons was confirmed in tissue culture analysis. The nature of the pretectal, midbrain and hindbrain regions expressing LacZ suggest that SCL in adult CNS is potentially involved in processing of visual, auditory and pain related information. During embryogenesis, LacZ expression was similarly confined to thalamus, midbrain and hindbrain. LacZ staining was also evident in parts of the intermediate and marginal zone of the aqueduct and ventricular zone of the fourth ventricle at E12.5 and E14. These cells may represent progenitor stages of differentiating neural cells. Given the presence of SCL in both the developing brain and in post-mitotic neurons, it seems likely that the function of SCL in neuronal differentiation may differ from its function in maintaining the differentiated state of the mature neuron.

Animals↗

PubMed2003

The effect of screw length and position on fixation of four-stranded hamstring grafts for anterior cruciate ligament reconstruction.

The aim of this study was to examine interference screw fixation of four strand hamstring grafts for anterior cruciate ligament reconstruction in vitro. Bovine tibiae and cannon tendons were used. Screws were introduced from 'outside-in'. The tendons were loaded cyclically to 150 N to simulate walking and 450 N to simulate jogging. Slippage of the tendon from the anchorage was recorded after 100, 300 and 1000 cycles. Cortico-cancellous and cancellous only fixations were compared using a 7-mm screw in an 8-mm tunnel with a 7-mm graft. The effect of screw length was studied by comparing 8 x 25 and 8 x 45 mm screws. Graft slippage with cancellous only fixation was significantly greater than with cortico-cancellous screw fixation (P 0.105), the longer screws gave more consistent behaviour. We concluded that the screw should be placed so that its head engages the cortex, while increasing screw length within cancellous bone did not significantly improve graft fixation. Cyclical load testing reflects the repetitive forces imposed in the early post-operative period following hamstring anterior cruciate ligament reconstruction and is important for the evaluation of graft fixations.

Animals↗

PubMed2002

Learning deficits in aged rats related to decrease in extracellular volume and loss of diffusion anisotropy in hippocampus.

The extracellular space (ECS) is the microenvironment of the nerve cells and an important communication channel, allowing for long-distance extrasynaptic communication between cells. Changes in ECS size, geometry, and composition have been reported in diverse (patho)physiological states, including aging. In the present study, real-time tetramethylammonium (TMA+) iontophoresis was used to quantify ECS diffusion parameters in different brain regions of adult and behaviorally characterized aged rats. Prior to ECS diffusion measurement, superior and inferior learners were selected from a large group of aged rats, according to their performance in the open-field water maze. The main finding was that the degree of impaired maze performance of old rats correlates, firstly, with decrease in ECS volume, loss of diffusion anisotropy in hippocampus, and degree of astrogliosis, and secondly, with disorganization of the astrocytic processes and reduction of hippocampal ECS matrix molecules. Importantly, no significant differences were found in the density of neurons in any region of the hippocampus or dentate gyrus. The alterations in hippocampal diffusion parameters evident in aged animals with severe learning deficits could account for the learning impairment, due to their effects on extrasynaptic volume transmission and/or on the "cross-talk" between synapses, which has been suggested to be involved in neural processes associated with learning and memory formation.

Aging↗

PubMed2002

Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: a comparison with lentiviral vectors.

Replication-deficient viral vectors encoding the marker gene green fluorescent protein (GFP) were injected into the vitreous of newborn, juvenile (P14), and adult rats. We tested two different types of modified virus: adeno-associated viral-2-GFP (AAV-GFP) and lentiviral-GFP vectors (LV-GFP). The extent of retinal cell transduction in different-aged animals was compared 7, 21, and 70 days after eye injections. At all postinjection times, LV-GFP transduction was mostly limited to pigment epithelium and cells in sclera and choroid. In contrast, transduction of large numbers of neural retinal cells was seen 21 and 70 days after AAV-GFP injections. AAV-GFP predominantly transduced neurons, although GFP-positive Müller cells were seen. All neuronal classes were labeled, but the extent of transduction for a given class varied depending on injection age. After P0 injections about 50% of transduced cells were photoreceptors and 30-40% were amacrine or bipolar cells. After adult injections 60-70% of transduced cells were retinal ganglion cells. In adults many GFP-positive retinal axons were traced through the optic nerve/tract and terminal arbors were visualized in central targets.

Adenoviridae↗

PubMed2002

Chronic gliosis triggers Alzheimer's disease-like processing of amyloid precursor protein.

Alzheimer's disease is a progressively dementing illness characterized by the extracellular accumulation and deposition of beta-amyloid. Early onset Alzheimer's disease is linked to mutations in three genes, all of which lead to increased beta-amyloid production. Inflammatory changes and gliosis may also play a role in the disease process, but the importance of these reactive events remains unclear. We recently reported that chronic cortical gliosis in heterotopic fetal rat cortical transplants is associated with significant changes in the levels of some of the proteins implicated in the pathogenesis of Alzheimer's disease. Because rodent beta-amyloid does not form extracellular amyloid deposits, we have now extended this model of chronic cortical gliosis to transgenic mice expressing the Swedish mutant form of human amyloid precursor protein. In addition, apolipoprotein E knockout mice were used to elucidate the role of this protein in reactive gliosis. The expression of mutant and murine proteins was assayed 6 or 10 months after transplantation using immunohistochemical and western blot methods. Heterotopic transplantation of fetal cortex onto the midbrain of neonatal mice consistently resulted in reactive gliosis, independent of apolipoprotein E status. In contrast, in homotopic cortex-to-cortex grafts there was little alteration in glial reactivity, a result similar to that obtained previously in rats. By 10 months post-transplantation the level of presenilin-1 expression was lower in heterotopic grafts than in host cortex and there was increased expression of transgenic amyloid precursor protein, but only in the gliotic cortex-to-midbrain grafts. Most importantly, increased levels of beta-amyloid, and particularly its precursor, C-99, were selectively found in these heterotopic transplants. Our results show that chronic gliosis is associated with altered processing of the amyloid precursor protein in vivo and thus may initiate or exacerbate pathological changes associated with Alzheimer's disease.

Alzheimer Disease↗

PubMed2002

Viral vector-mediated gene expression in olfactory ensheathing glia implants in the lesioned rat spinal cord.

Implantation of olfactory ensheathing glia (OEG) is a promising strategy to augment long-distance regeneration in the injured spinal cord. In this study, implantation of OEG following unilateral hemisection of the dorsal cervical spinal cord was combined with ex vivo gene transfer techniques. We report, to our knowledge for the first time, that purified cultures of primary OEG are capable of expressing a foreign gene following adenoviral (AdV) and lentiviral (LV) vector-mediated gene transfer. OEG implants subjected to AdV vector-mediated gene transfer expressed high levels of transgenic protein in both intact and lesioned spinal cord at 7 days after implantation. However, the levels of transgene expression gradually declined between 7 and 30 days after implantation in lesioned spinal cord. Infection with LV vectors resulted in stable transduction of primary OEG cultures and transgene expression persisted for at least 4 months after implantation. Genetic engineering of OEG opens the possibility of expressing additional neurotrophic genes and create optimal 'bridging' substrates to support spinal axon regeneration. Furthermore, stable transduction of OEG allows us to reliably study the behaviour of implanted cells and to obtain better understanding of their regeneration supporting properties.

Adenoviridae↗

PubMed2001

The regrowth of axons within tissue defects in the CNS is promoted by implanted hydrogel matrices that contain BDNF and CNTF producing fibroblasts.

In this study we demonstrate the potential for combining biocompatible polymers with genetically engineered cells to elicit axon regrowth across tissue defects in the injured CNS. Eighteen- to 21-day-old rats received implants of poly N-(2-hydroxypropyl)-methacrylamide (HPMA) hydrogels containing RGD peptide sequences that had been infiltrated with control (untransfected) fibroblasts (n = 8), fibroblasts engineered to express brain-derived neurotrophic factor (BDNF) (n = 5), ciliary neurotrophic factor (CNTF) (n = 5), or a mixture of BDNF and CNTF expressing fibroblasts (n = 11). Fibroblasts were prelabeled with Hoechst 33342. Cell/polymer constructs were inserted into cavities made in the left optic tract, between thalamus and superior colliculus. After 4-8 weeks, retinal projections were analyzed by injecting right eyes with cholera toxin (B-subunit). Rats were perfused 24 h later and sections were immunoreacted to visualize retinal axons, other axons (RT97 antibody), host astrocytes and macrophages, donor fibroblasts, and extracellular matrix molecules. The volume fraction (VF) of each gel that was occupied by RT97(+) axons was quantified. RT-PCR confirmed expression of the transgenes prior to, and 5 weeks after, transplantation. Compared to control rats (mean VF = 0.02 +/- 0.01% SEM) there was increased ingrowth of RT97(+) axons into implants in CNTF (mean VF = 0.33 +/- 0.19%) and BDNF (mean VF = 0.62 +/-0.19%) groups. Axon growth into hydrogels in the mixed BDNF/CNTF group (mean VF = 3.58 +/- 0.92%) was significantly greater (P < 0.05) than in the BDNF or CNTF fibroblast groups. Retinal axons exhibited a complex branching pattern within gels containing BDNF or BDNF/CNTF fibroblasts; however, they regrew the greatest distances within implants containing both BDNF and CNTF expressing cells.

Animals↗

PubMed2001

Reinnervation of the superior colliculus delays down-regulation of ephrin A2 in neonatal rat.

Although the adult mammalian optic nerve does not regenerate following lesion, in the neonatal rat, retinal ganglion cell (RGC) axons retain the capacity to grow across lesion sites in the brain. Following a brachial lesion at postnatal day 2 (P2), some RGC axons, together with ingrowing cortico-tectal axons, cross the lesion to reinnervate the superior colliculus (SC). Here we use immunohistochemistry to examine expression of the guidance cue ephrin A2 following a brachial lesion. Normal animals show a steady decrease in ephrin A2 immunoreactivity between P5 and P31, with a low rostral to high caudal gradient being evident only at P5. By contrast, after brachial lesion, values are significantly elevated rostrally at P5 and caudally at P12; moreover, a steep rostro-caudal gradient is present at both ages. By P31 values fall to normal levels. Following unilateral enucleation at P2, levels are not significantly different from normal. Our results show that innervation but not denervation triggers increased ephrin A2 expression after a brachial lesion.

Animals↗

PubMed2001

Expression of messenger RNAs for glutamic acid decarboxylase, preprotachykinin, cholecystokinin, somatostatin, proenkephalin and neuropeptide Y in the adult rat superior colliculus.

The mammalian superior colliculus is an important subcortical integrator of sensorimotor behaviours. It is multi-layered, each layer containing specific neuronal types and possessing distinct input/output relationships. Here we use in situ hybridisation methods to map the distribution of seven neurotransmitters/neuromodulator systems in adult rat superior colliculus. Coronal sections were probed for preprotachykinin, cholecystokinin, somatostatin, proenkephalin, neuropeptide Y and the enzymes glutamic acid decarboxylase and choline acetyltransferase, markers for GABA and acetylcholine respectively. Cells expressing glutamic acid decarboxylase messenger RNA were the most abundant, the highest density being found in the superficial layers. Many cells containing proprotachykinin messenger RNA were found in stratum zonale and the upper two-thirds of stratum griseum superficiale; cells were also located in deeper tectal laminae, particularly caudomedially. Most cholecystokinin messenger RNA expressing cells were located in the superficial layers with a prominent band in the middle third of stratum griseum superficiale. Cells expressing moderate to high levels of somatostatin messenger RNA formed a dense band in the lower third of stratum griseum superficiale/upper stratum opticum; two less distinct tiers of labelling were seen in deeper layers. These in situ hybridisation data reveal three distinct sub-laminae in rat stratum griseum superficiale. Cells expressing moderate to low levels of proenkephalin messenger RNA were located in lower stratum griseum superficiale/upper stratum opticum and intermediate laminae. A cluster of enkephalinergic cells was located medially in the deep tectal laminae. Expression of neuropeptide Y messenger RNA was relatively low and mostly confined to cells in stratum griseum superficiale and stratum opticum. No choline acetyltransferase messenger RNA was detected. This in situ analysis of seven different neurotransmitters/neuromodulator systems sheds new light on the neurochemical organisation of the rat superior colliculus. The data are related to what is known anatomically and physiologically about intrinsic and extrinsic tectal circuitry, and the potential involvement of different neuropeptides in these circuits is discussed. The work forms the basis for future developmental studies examining the effects of transplantation and visual deprivation/deafferentation on tectal neurochemistry and function.

Age Factors↗

PubMed2001

Altered expression of apolipoprotein E, amyloid precursor protein and presenilin-1 is associated with chronic reactive gliosis in rat cortical tissue.

A major characteristic feature of Alzheimer's disease is the formation of compact, extracellular deposits of beta-amyloid (senile plaques). These deposits are surrounded by reactive astrocytes, microglia and dystrophic neurites. Mutations in three genes have been implicated in early-onset familial Alzheimer's disease. However, inflammatory changes and astrogliosis are also believed to play a role in Alzheimer's pathology. What is unclear is the extent to which these factors initiate or contribute to the disease progression. Previous rat studies demonstrated that heterotopic transplantation of foetal cortical tissue onto the midbrain of neonatal hosts resulted in sustained glial reactivity for many months. Similar changes were not seen in cortex-to-cortex grafts. Using this model of chronic cortical gliosis, we have now measured reactive changes in the levels of the key Alzheimer's disease proteins, namely the amyloid precursor protein, apolipoprotein E and presenilin-1. These changes were visualised immunohistochemically and were quantified by western blot analysis. We report here that chronic cortical gliosis in the rat results in a sustained increase in the levels of apolipoprotein E and total amyloid precursor protein. Reactive astrocytes in heterotopic cortical grafts were immunopositive for both of these proteins. Using a panel of amyloid precursor protein antibodies we demonstrate that chronic reactive gliosis is associated with alternative cleavage of the peptide. No significant changes in apolipoprotein E or amyloid precursor protein expression were seen in non-gliotic cortex-to-cortex transplants. Compared to host cortex, the levels of both N-terminal and C-terminal fragments of presenilin-1 were significantly lower in gliotic heterotopic grafts.The changes described here largely mirror those seen in the cerebral cortex of humans with Alzheimer's disease and are consistent with the proposal that astrogliosis may be an important factor in the pathogenesis of this disease.

Alzheimer Disease↗

PubMed2001

Migration of cells into and out of peripheral nerve isografts in the peripheral and central nervous systems of the adult mouse.

Peripheral nerve (PN) isografts provide a favourable environment for axon regeneration after peripheral and central nervous system (CNS) injury, but definitive information on the extent of cellular intermixing between donor and host tissues is lacking. We wished to compare migration patterns in fresh and predegenerate PN grafts, and also compare the extent of cell migration after transplantation to peripheral nervous system (PNS) versus CNS. To discern how host and donor cells interact after PN transplantation, sciatic nerve segments were transplanted from inbred adult mice into PN defects (PN-PN grafts) or into lesioned cerebral cortex of opposite gender siblings. Migrating male cells were identified using a Y-chromosome-specific probe and in situ hybridization methods, and characterized immunohistochemically. The extent of donor and host cellular intermixing was similar in fresh and predegenerate PN-PN isografts. There was substantial intermixing of donor and host cells by 8 days. Many host cells migrating into epineurial regions of grafts were immunopositive for F4/80 (macrophages). The endoneurium of grafted PN was also colonized by host cells; some were F4/80+ but many were immunostained with S-100 (Schwann cell marker). Donor S-100+ Schwann cells rapidly migrated out into proximal and distal host PN and by 12 weeks were found at least 2 mm from the grafts. Endoneurial microvessels in grafts were mostly donor-derived. By comparison, in male PN grafts to female CNS, even after 6 weeks few donor cells had migrated out into surrounding host cortex, despite the observation that almost all grafts contained regenerating axons and were thus attached to host CNS tissue.

Animals↗