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K Horsburgh

Publications and source records attributed to K Horsburgh.

At least 19 recordsLinked to original sources
PubMed2001

Minimal ischaemic neuronal damage and HSP70 expression in MF1 strain mice following bilateral common carotid artery occlusion.

Investigation into the influence of specific genes and gene products upon the pathophysiology of cerebral ischaemia has been greatly enhanced by the use of genetically modified mice. A simple model of global cerebral ischaemia in mouse is bilateral common carotid artery occlusion (BCCAo) and the neuropathological impact of BCCAo has been investigated in several mouse strains. Bilateral carotid occlusion produces extensive neuronal damage in C57Bl/6J strain mice and this damage is linked to posterior communicating artery (PcomA) hypoplasticity in the circle of Willis. In the present study, we investigated the effect of BCCAo in MF1 strain mice and compared them with C57Bl/6J mice. The neuropathological consequences of BCCAo were assessed using standard histochemical staining and heat shock protein 70 (HSP70) immunohistochemical staining (to demarcate cells that had been ischaemically stressed). The effect of BCCAo on mean arterial blood pressure (MABP) was also measured. The plasticity of the circle of Willis was recorded using carbon black perfusion. MF1 mice displayed significantly less ischaemic neuronal damage and HSP70 immunoreactivity compared to C57Bl/6J mice following 10-20 min BCCAo. Moreover, ischaemic neuronal damage and HSP70 immunoreactivity in MF1 mice subjected to extended BCCAo (25-45 min) was never as extensive or widespread as that observed in C57Bl/6J mice after 20 min BCCAo. MABP in MF1 mice (102+/-5 mmHg) was significantly higher than in C57Bl/6J mice (87+/-5) during 20 min BCCAo. MABP in MF1 mice during 20 and 40 min (103+/-12 mmHg) BCCAo remained above pre-occlusion values for the entire occlusion period. MF1 mice had significantly greater circle of Willis plasticity (more PcomAs) than C57Bl/6J mice did. These data indicate that MF1 mice are less susceptible to BCCAo than C57Bl/6J mice and that this could be due to maintained increases in MABP during BCCAo and the lower prevalence of abnormalities of the circle of Willis in MF1 mice.

Animals↗
PubMed2001

Alterations in ApoE and ApoJ in relation to degeneration and regeneration in a mouse model of entorhinal cortex lesion.

Apolipoproteins are primarily involved in the transport of lipid and cholesterol within the central nervous system (CNS) and are thought to play a role in synaptic remodeling, repair, and regeneration after brain injury. In the present study, alterations in apolipoproteins E (apoE) and J (apoJ) were examined in the molecular layers of the dentate gyrus after unilateral chemical lesioning of the entorhinal cortex (ECL), at days 0, 1, 3, 7, 28, and 90 days following injury. Alterations in immunostaining for these proteins were assessed in relation to accumulation of silver-labeled degeneration products and alterations in synaptophysin and GAP-43 immunoreactivity. Quantitative analysis of synaptophysin and GAP-43 immunostaining highlighted synaptic loss and fiber degeneration initially (3-7 days post-ECL), with subsequent terminal sprouting and reactive synaptogenesis occurring at longer survival periods (28-90 days post-ECL). Increased apoE and apoJ immunoreactivity was evident first within the neuropil (*P < 0.05 and **P < 0.01) followed by intense glial staining by day 7 post-ECL. By day 28 apoE and apoJ immunostaining had returned almost to baseline levels. However, at day 90 post-ECL, neuropil apoE and apoJ immunoreactivity was dramatically increased compared to contralateral levels (**P < 0.01 and ***P < 0.0001, respectively). Silver-labeled degeneration products were found to be in abundance at day 3 postlesion; however, by day 7 this was reduced leaving only a thin band of material within the MML and at day 90 post-ECL, dentate silver staining was similar to that of controls. The results indicate that apoE and apoJ are upregulated after injury and parallel clearance of cholesterol and lipid debris from the site of injury. This coordinated alteration in apolipoproteins may redistribute lipid material to sprouting fibers to promote neurite extension and may play an important role in long-term plasticity changes following injury.

Animals↗
PubMed2001

Impaired neuronal plasticity in transgenic mice expressing human apolipoprotein E4 compared to E3 in a model of entorhinal cortex lesion.

The apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for late-onset familial and sporadic Alzheimer's disease (AD) and is associated with a poor outcome after brain injury. Each apoE isoform is suggested to have differential effects on neuronal repair mechanisms within the CNS. In the present study, APOE genotype influence on the immediate response to injury and subsequent repair process was examined in a line of transgenic APOE mice possessing human APOE gene insertions (epsilon 3 and epsilon 4). Quantification of synaptophysin and GAP-43 immunoreactivity was used to measure the extent of degeneration and regeneration after entorhinal cortex lesion (ECL). Progressive neurodegenerative decline occurred in the ipsilateral dentate gyrus until day 28 post-ECL which was more severe in APOE epsilon 3 mice compared to APOE epsilon 4 mice. By day 90 post-ECL compensatory sprouting and reactive synaptogenesis had taken place in the dentate gyrus of APOE epsilon 3 mice such that GAP-43 and synaptophysin immunoreactivity had returned to prelesion levels. In contrast, APOE epsilon 4 mice displayed significant deficits in synaptophysin and GAP-43 immunostaining compared to the APOE epsilon 3 mice (P < 0.05). Expansion of the inner molecular layer (IML) was used as a measure of the sprouting index from the commissural-associational pathway and by day 90 post-ECL the IML width in APOE epsilon 3 mice had increased by 45% but only 20% in APOE epsilon 4 mice (P < 0.0001). ApoE immunoreactivity was increased within the neuropil and glia to the same extent in APOE epsilon 3 and APOE epsilon 4 mice post-ECL. There was no significant difference in the deposition and clearance of degeneration products between APOE epsilon 3 and epsilon 4 mice post-ECL. These results indicate that neuronal plasticity is impaired in transgenic mice possessing human APOE epsilon 4 alleles compared to APOE epsilon 3. These isoform-specific differences in plasticity may relate to the severity of AD and poor, long-term recovery after head injury in APOE epsilon 4 individuals.

Alzheimer Disease↗
PubMed2001

Targeting expression of hsp70i to discrete neuronal populations using the Lmo-1 promoter: assessment of the neuroprotective effects of hsp70i in vivo and in vitro.

Transgenic technology provides a powerful means of studying gene regulation and specific gene function with complex mammalian systems. In this study, the authors exploited the specific and discrete neuronal expression pattern mediated by promoter 1 of the Lmo-1 gene to study the neuroprotective effects of the inducible form of heat shock protein 70kD (hsp70i) in primary hippocampal cultures in a mouse model of global cerebral ischemia. Targeting expression of hsp70i to hippocampal neurons protected these cells significantly from toxic levels of glutamate and oxidative stress (for example, exposure to 10 micromol/L free iron produced a 26% increase in lactate dehydrogenase release from neurons cultured from wild-type mice, but a 7% increase in neurons cultured from hsp70i transgenic mice). Bilateral carotid occlusion (25 minutes) produced significantly less neuronal damage in the caudate nucleus and posterior thalamus in hsp70i transgenic mice than in wild-type littermates (for example, 21% +/- 9.3% and 12.5% +/- 9.0% neuronal damage in lateral caudate nucleus of wild-type and hsp70i transgenic mice, respectively, P < 0.05). The current study highlights the utility of targeted expression of transgenes of interest in cerebral ischemia and demonstrates that expression of hsp70i alone is sufficient to mediate the protection of primary neurons from denaturing stress and that expression of human hsp70i in vivo plays crucial role in determining the fate of neurons after ischemic challenge.

Animals↗
PubMed2001

4-Hydroxynonenal immunoreactivity is increased in human hippocampus after global ischemia.

Oxidative stress and lipid peroxidation may contribute to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD) and cerebral ischemia. 4-Hydroxynonenal (4-HNE) is a toxic by-product of lipid peroxidation, and immunoreactivity to 4-HNE has been used to examine lipid peroxidation in the pathogenesis of AD and ischemia. This study sought to determine 1) if there are cellular alterations in 4-HNE immunoreactivity in the human hippocampus after global ischemia, and 2) whether possession of an apolipoprotein E (APOE) epsilon4 allele influenced the extent of 4-HNE immunoreactivity. 4-HNE immunoreactivity was assessed semi-quantitatively in the temporal lobe of a group of controls (n = 44) and in a group of patients who had an episode of global ischemia as a result of a cardiorespiratory arrest and subsequently died (n = 56, survival ranged from 1hr to 42 days). There was minimal cellular 4-HNE immunoreactivity in the control group. However, compared to controls, 4-HNE immunoreactivity was significantly increased in neurons (p < 0.0002) and glia (p < 0.0001) in the hippocampal formation after global ischemia. Possession of an APOE epsilon4 allele did not influence the extent of neuronal or glial 4-HNE immunostaining in the control or global ischemia group. There was a significant negative correlation between the extent of neuronal 4-HNE immunoreactivity with survival period after global ischemia (r2 = 0.0801; p < 0.036) and a significant positive correlation between the extent of glial 4-HNE immunoreactivity and survival after global ischemia (r2 = 0.2958; p < 0.0001). The data indicate a marked increase in neuronal and glial 4-HNE. This substantiates a role for lipid peroxidation in the pathogenesis of cerebral ischemia. There was no indication that APOE genotype influenced the extent of 4-HNE immunoreactivity.

Adolescent↗
PubMed2000

beta-amyloid (Abeta)42(43), abeta42, abeta40 and apoE immunostaining of plaques in fatal head injury.

beta-Amyloid (Abeta) deposits are found in the brains of approximately one-third of patients who die within days after a severe head injury; their presence correlating strongly with possession of an apolipoprotein E (apoE)-epsilon4 allele. The aim of the study was to investigate the relationship between Abeta42, Abeta40 and apoE immunostaining of Abeta plaques in the cerebral cortex and the relevance of apoE genotype in 23 fatally head-injured patients. These cases were known to have Abeta deposits from a previous study in which they were examined and semiquantified and related to apoE genotype. In the present study, the temporal cortex was probed using four different antibodies that recognize Abeta42(43), Abeta40 and an antibody to apoE. Abeta42(43)-positive plaques were observed in all of the 23 cases and Abeta40 immunoreactivity in only 11 of the 23 cases. In addition, semiquantitative analysis showed that relatively fewer plaques were detected with anti-Abeta40 than anti-Abeta42(43). ApoE-immunoreactive plaques were identified in 18 of the 23 cases. The number of plaques stained for apoE was relatively less than for Abeta42(43) but greater than for Abeta40. Furthermore, the density of Abeta plaques detected using either Abeta42(43), Abeta40 or apoE antibodies was associated with possession of apoE-epsilon4 in an allele dose-dependent manner. The results are consistent with Abeta42(43) as the initially deposited species in brain parenchyma and provide evidence that apoE is involved in the early stages of amyloid deposition. Further, the findings may be of relevance to the role of apoE genotype in influencing outcome after acute brain injury.

Adolescent↗
PubMed2000

Intraventricular infusion of apolipoprotein E ameliorates acute neuronal damage after global cerebral ischemia in mice.

The ability of intraventricular infusion of apolipoprotein E (apoE) to reduce neuronal damage after global cerebral ischemia was investigated in apoE-deficient and wild-type mice. ApoE (5 microg/mL lipid-conjugated derived from human plasma; 1 microL/h, continuous infusion) significantly reduced neuronal damage in the caudate nucleus and CA2 pyramidal cell layer by approximately 50% in apoE-deficient mice after global ischemia compared to vehicle infusion. In wild-type mice infused with apoE, there was a trend for ischemic neuronal damage to be reduced. ApoE-infused mice had a marked reduction in 4-hydroxynonenal immunoreactivity, as a marker of lipid peroxidation. The results show that the presence of apoE at or after the time of injury can be neuroprotective, possibly via an anti-oxidant mechanism.

Aldehydes↗
PubMed2000

Increased neuronal damage and apoE immunoreactivity in human apolipoprotein E, E4 isoform-specific, transgenic mice after global cerebral ischaemia.

Apolipoprotein E (apoE, protein; APOE, gene) is expressed as three isoforms in humans (E2, E3, E4). The APOE-epsilon4 allele is associated with a poor outcome in patients after head injury of which ischaemic brain damage is a contributor of mortality and morbidity. The aim of the study was to determine whether mice expressing human APOE-epsilon4 displayed more extensive ischaemic neuronal damage 72 h after transient global ischaemia compared with mice which express human APOE-epsilon3. APOE-epsilon3 and -epsilon4 transgenic mice, under the control of a human promoter, were used which express human APOE in neurons and glia. Ischaemic neuronal damage in the CA1 pyramidal cell layer in the APOE-epsilon4 transgenic mice was significantly greater than in the APOE-epsilon3 mice after global ischaemia (36.4+/-8.9%, 18.2+/-7.3%; P<0.05). This was associated with more extensive neuronal apoE immunoreactivity in the CA1 pyramidal cell layer in the APOE-epsilon4 transgenic mice compared with APOE-epsilon3 transgenic mice. In contrast, in the caudate nucleus, there were similar levels of ischaemic neuronal damage in the APOE-epsilon3 and -epsilon4 transgenic mice (39.2 +/-10.1%; 44.6+/-8.4%, P = 0.32). In the caudate, similar numbers of neurons were immunostained for apoE in the APOE-epsilon3 and -epsilon4 transgenic mice. The present study demonstrated that the APOE-epsilon4 allele is associated with an increased vulnerability of a specific brain region to the effects of global ischaemia, which is closely associated with an increase in neuronal apoE. The data extend previous work and are consistent with an association of the APOE-epsilon4 allele with a poor outcome after acute brain injury in humans.

Alleles↗
PubMed1999

Increased neuronal damage in apolipoprotein E-deficient mice following global ischaemia.

There is accumulating evidence that apolipoprotein E (apoE) plays a role in regulating the response to and outcome following brain injury. The present study compared the histological outcome and recovery following an episode of global ischaemia in apoE-deficient mice and wild-type littermates (12-week-old males, n = 8 per group). Transient global ischaemia was induced for a period of 17 min and the animals were allowed to recover for 72 h. Transient global ischaemia induced selective neuronal degeneration in several brain regions in wild-type mice. There was statistically significant increased ischaemic neuronal damage in apoE-deficient mice compared with wild-type mice in six of the seven regions examined (hippocampal regions CA1, CA3/CA4 and dentate gyrus; thalamus; cortex and caudate nucleus; P < 0.05). The data substantiate a role for apoE in modifying the response of the CNS to acute injury.

Alleles↗
PubMed1999

Apolipoprotein E and the response of the brain to injury.

Apolipoprotein E (apoE) is an important part of the means by which lipids are transported in the nervous system. This transport system provides injured nerve cells, the cholesterol and phospholipids for the maintenance and repair of membranes, the growth of neurites, dendritic remodelling and synaptogenesis, and the effect of injury to the nervous system is now known in part to be modulated by the various isoforms of apoE. After the demonstration of an association between the apoE epsilon 4 and increased risk of subsequent development of both sporadic and late-onset form Alzheimer's disease, recent studies have provided additional evidence for the possibility that apoE may play an isoform-specific role in determining both the initial response and the subsequent consequences to acute brain injury. Further studies are required to better understand not only the response(s) of the nervous system to injury, but also the relationship between acute injury to the brain and the subsequent development of neurodegenerative disorders.

Alzheimer Disease↗
PubMed1999

Influence of apolipoprotein E genotype on neuronal damage and apoE immunoreactivity in human hippocampus following global ischemia.

Apolipoprotein E (apoE) influences the response to and outcome from brain injury possibly through alterations in neuronal repair mechanisms. This study aimed to determine alterations in neuronal and glial apoE after brain injury in patients and sought to determine whether possession of an apoE-epsilon4 allele influences the degree of apoE immunoreactivity or the degree of neuronal damage following brain injury. ApoE immunoreactivity and neuronal damage were semiquantitatively assessed in the temporal lobe of a group of controls (n = 44) and in a group of patients who had an episode of global ischemia and subsequently died (n = 58, survival ranged from 1 hour to 3 months). There was a significant degree of neuronal damage in all hippocampal sectors and in the neocortex of the global ischemia group compared with controls (p < 0.0001). Glial apoE immunoreactivity was significantly increased in hippocampal sectors (CA1, CA2, CA3/CA4, dentate fascia) in the global ischemia group compared with controls (p < 0.01). Neuronal apoE immunoreactivity was significantly increased in all hippocampal sectors (CA1, CA2, CA3/CA4, dentate fascia) and in the neocortex of the global ischemia group compared with controls (p < 0.0001). There was a significant and positive association between the degree of neuronal apoE immunoreactivity and the degree of neuronal damage in the global ischemia cases (r2 = 0.691, p < 0.001) and there was not an association in the control group. Possession of an apoE-epsilon4 allele did not influence the degree of neuronal or glial apoE immunoreactivity or the degree of neuronal damage in the global ischemia cases or the controls. The data indicate apoE is markedly increased in neurons and glia following brain injury. In this study, apoE genotype did not appear to influence neuronal damage, glial apoE or intraneuronal apoE following injury

Adolescent↗
PubMed1998

Apolipoprotein E and the CNS response to injury.

Apolipoprotein E (apoE) is a multifunctional protein with an expanding role in the neurobiology of disease. Although originally described in the context of cholesterol metabolism, interest in the neurobiology of apoE has intensified following the association between apoE genotype and risk of developing Alzheimer's disease. Recent clinical observations also suggest that apoE genotype may influence recovery after a variety of neurological insults. Thus, in addition to the study of disease-specific mechanisms by which apoE may modulate susceptibility of developing Alzheimer's disease, there has been an increasing focus on its role in modulating the CNS response to acute injury. Although the neurobiology of apoE in the injured brain remains incompletely defined, there is evidence to suggest neurotrophic, immunomodulatory, and antioxidant effects.

Alzheimer Disease↗
PubMed1997

Marked alterations in the cellular localisation and levels of apolipoprotein E following acute subdural haematoma in rat.

Apolipoprotein E (apoE) plays a role in the response to acute brain injury, the mechanisms as yet remain unknown. In the present study, alterations in the immunohistochemical localisation of apoE in rat cortex were examined at 30 min, 2 h or 4 h following production of an acute subdural haematoma. Levels of apoE were determined in cortex by immunoblotting at 30 min and 4 h post-haematoma. Extensive areas of ischaemic cell damage were observed in the cortex underlying the haematoma with minimal damage observed in shams. In sham animals, apoE immunoreactivity was confined to astrocytes and their processes. Following the haematoma induction, apoE immunoreactivity was dramatically altered. At 30 min post-haematoma, intense apoE staining was observed in clusters of neuronal perikarya and the neuropil throughout the cortical layers underlying the haematoma and this persisted at 2 h and 4 h post-haematoma. Additionally, at 4 h post-haematoma marked apoE staining of discrete foci within the neuropil closely associated with capillaries was consistently observed in the ipsilateral cortex. Immunoblotting indicated there were no significant alterations in the cortical levels of apoE at 30 min post-haematoma but, at 4 h post-haematoma, there was a significant elevation (27%, P < 0.001) in the levels of apoE in cortex underlying the haematoma compared to control levels. The results indicate that following acute subdural haematoma, a rapid cellular redistribution of apoE occurs and precedes a significant elevation in the levels of apoE. These alterations in apoE may occur, at least initially, as part of the brain's protective response to injury.

Animals↗
PubMed1997

Intracortical glutamate perfusion in vivo induces cellular alterations in specific protein kinase C isoforms and amyloid precursor protein.

This study investigated the immunostaining of protein kinase C (PKC) isoforms and amyloid precursor protein (APP) in rat brain cortex and determined alterations following an excitotoxic challenge in vivo. Cellular alterations in APP and PKC isoforms (alpha, beta, gamma, delta, epsilon, and zeta) following glutamate perfusion in the rat parietal cortex were compared with NaCl perfusion. In all animals, two histological zones could be defined consistently, a necrotic core and a boundary zone immediately adjacent to the core. Following glutamate and NaCl perfusion, cellular immunoreactivity to PKC isoforms and amino-terminal APP was significantly reduced within the necrotic core. Striking carboxy-terminal APP immunoreactivity was observed in some neurons remaining within the necrotic core. In the boundary of the glutamate lesion, the perikarya of most neurons were intensely immunoreactive to PKC alpha and beta. Furthermore, within the boundary zone, enhanced immunoreactivity within neuronal perikarya was observed to amino-terminal APP and, to a lesser extent, carboxy-terminal APP. Increased immunostaining of PKC alpha and beta and APP at the boundary zone was a consistent feature of intracortical glutamate perfusion and was not observed following NaCl perfusion. There were minimal alterations in PKC isoforms gamma, delta, epsilon, and zeta, in the boundary region following intracortical glutamate or NaCl perfusion. There was no astrocytic response, as detected by GFAP immunoreactivity, at the boundary zone. These findings indicate that there is a topographical relationship between cellular alterations of specific PKC isoforms and APP following an excitotoxic challenge in vivo.

Amyloid beta-Protein Precursor↗
PubMed1996

Selective alterations in the cellular distribution of apolipoprotein E immunoreactivity following transient cerebral ischaemia in the rat.

The aim of this study was to examine the cellular localization and alterations of apolipoprotein E (apoE) following a transient ischaemic insult using immunohistochemistry. Transient cerebral ischaemia was induced in Wistar rats by occlusion of both carotid arteries with hypotension followed by reperfusion for 4 h (n = 5), 24 h (n = 5) or 72 h (n = 6). In sham-operated animals (n = 9), the carotids were not occluded. In this model, ischaemia for 15 min results in selective neuronal damage in the caudate nucleus and neocortex (24 h after reperfusion) and the hippocampal CA1 pyramidal cells (72 h after reperfusion) while there is minimal damage in other areas such as the CA3 hippocampal region. In sham animals apoE immunoreactivity was confined to astrocytes and their processes. ApoE immunoreactivity was not altered at 4 h post-ischemic reperfusion. At 24 h reperfusion, intense apoE staining of the cytoplasm of astrocytes and neuropil within the caudate and neocortex was observed and at 72 h reperfusion apoE stained neuronal cell bodies within these regions. Within the CA1 region at 24 h reperfusion, there was increased immunoreactivity of the cytoplasm of astrocytes and the neuropil was more intensely stained compared with sham animals. At 72 h reperfusion, intense apoE staining of pyramidal cell bodies and dendrites was consistently observed in the CA1 region of the hippocampus. In contrast, at 72 h reperfusion, apoE staining of astrocytic processes was dramatically reduced in the CA1 region although GFAP staining indicated their preservation. The results demonstrate that following an ischaemic insult apoE is localized to degenerating neurons and their processes. This may indicate an inherent protective response of cells to injury. Alternatively, the results are consistent with the hypothesis that apoE is synthesized and released by astrocytes and taken up by neurons following injury.

Animals↗
PubMed1993

Hyperactivation of signal transduction systems in Alzheimer's disease.

A compromise or deregulation in signal transduction cascades could adversely affect cellular functions and possibly contribute to cell death. In recent years, it has become increasingly apparent that pronounced activation of neuronal signal transduction systems is a characteristic of AD brain. There is evidence that signal transduction systems play a role in the formation or development of these pathological features of AD. Aberrant activity and localization of components of signaling mechanisms (growth factors, their receptors, protein kinases, phosphoprotein phosphatases, and phosphoproteins) are closely associated with the intracellular accumulation of PHF, the extracellular deposition of amyloid, and the formation of neuritic plaques in AD brain. In particular, immunohistochemical studies reveal increased levels of neuronal staining for APP, possibly an important growth factor in AD, both in frontal cortex and hippocampus. Anti-APP immunostaining is also associated with the neuritic component of plaques. Additionally, PKC(beta II) immunostaining is increased in the neuronal cell body and neuropil of AD samples, particularly in association with plaques, suggesting a postsynaptic involvement of this enzyme. On the other hand, PKC(beta I) immunostaining is associated with axonal staining particularly in the sprouting neurites of plaques. Sprouting neuritic components of plaques are immunopositive with other growth-associated proteins, such as GAP43, MARCKS, and spectrin. Immunoreactivity of other members of signal transduction systems such as Fos and stathmin are all increased in AD hippocampal neurons. On the other hand, several protein kinases and phosphoproteins were immunolocalized to tangles. Thus, the hyperactivation and dysfunction of signal transduction systems could be involved in the pathogenesis of AD.

Alzheimer Disease↗