Neuregulin signaling in brain injury and in animal models of ischemia.
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Animals↗
Biomedical subjects
D Dewar
Publications and source records attributed to D Dewar.
Topographical and quantitative assessment of white matter injury following a focal ischaemic lesion in the rat brain.
Axonal injury following cerebral ischaemia has attracted less attention than damage in grey matter. However, it is becoming increasingly recognised that axons are highly vulnerable to focal ischaemia [D. Dewar, D.A. Dawson, Changes of cytoskeletal protein immunostaining in myelinated fibre tracts after focal cerebral ischaemia in the rat, Acta. Neuropathol., 93 (1997) 71-77] [2]; [L. Pantoni, J.H. Garcia, J.A. Gutierrez, Cerebral white matter is highly vulnerable to ischemia, Stroke, 27 (1996) 1641-1647] [10]; [P. S. Yam, T. Takasago, D. Dewar, D.I. Graham, J. McCulloch, Amyloid precursor protein accumulates in white matter at the margin of a focal ischaemic lesion, Brain Res., 760 (1997) 150-157] [15]. Since white matter does not contain neuronal cell bodies or synapses it is likely that the mechanisms of injury and strategies for its protection are different from those in grey matter. In order that the effect of therapeutic intervention on the protection of axons can be assessed, a method by which axonal injury can be mapped and quantified is required. For this purpose, we investigated immunocytochemical methods using amyloid precursor protein (APP) following permanent middle cerebral artery occlusion in the rat. APP is transported by fast anterograde axonal transport [E.H. Koo, S.S. Sisodia, D.R. Archer, L.J. Martin, A. Weidemann, K. Beyreuther, P. Fischer, C.L. Masters, D.L. Price, Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport, Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 1561-1565] [7] and has been shown to accumulate following a variety of insults to axons, indicative of dysfunction of axonal transport [R.N. Kalaria, S.U. Bhatti, E.A. Palatinsky, D.H. Pennington, E.R. Shelton, H.W. Chan, G. Perry, W.D. Lust, Accumulation of the beta amyloid precursor protein at sites of ischemic injury in rat brain, Neuroreport, 4 (1993) 211-214] [4]; [T. Kawarabayashi, M. Shoji, Y. Harigaya, H. Yamaguchi, S. Hirai, Expression of APP in the early stage of brain damage, Brain Res., 563 (1991) 334-338] [5]; [N. Otsuka, M. Tomonaga, K. Ikeda, Rapid appearance of beta-amyloid precursor protein immunoreactivity in damaged axons and reactive glial cells in rat brain following needle stab injury, Brain Res., 568 (1991) 335-338] [9]; [K. Shigematsu, P. L. McGeer, Accumulation of amyloid precursor protein in neurons after intraventricular injection of colchicine, Am. J. Pathol., 140 (1992) 787-794] [12]. We have been able to map the topographical relationship between APP accumulation and region of infarction using immunocytochemistry and image analysis techniques. Additionally, using a semi-quantitative scoring system, we have demonstrated that there is a relationship between the amount of APP accumulation and the volume of infarction following middle cerebral artery occlusion. These methods will be useful in the future for the assessment of therapeutic interventions on the protection of axons following ischaemic injury.
Amyloid beta-Protein Precursor↗
The neuronal cytoskeleton in acute brain injury.
The microtubules, neurofilaments and microfilaments of the neuronal cytoskeleton are essential for the normal functioning of the neurone. Recent studies have shown that disruption of the cytoskeleton may represent a final pathway in many types of neuronal cell injury with both the somato-dendritic and axonal cytoskeleton being affected. This review discusses the current evidence on the role of the neuronal cytoskeleton in the pathogenesis of traumatic brain damage.
Brain Injuries↗
Cortical cholinergic dysfunction after human head injury.
Loss of cholinergic neurotransmission is implicated in memory impairment and cognitive dysfunction after head injury. The aim of the present study was to investigate presynaptic markers, particularly in relation to cholinergic neurotransmission in human postmortem brain from patients who died following a head injury and age-matched controls. Choline acetyltransferase activity and high-affinity nicotinic receptor binding sites were assayed in the inferior temporal gyrus, cingulate gyrus, and superior parietal cortex of 16 head-injured patients and 8 controls. Synaptophysin immunoreactivity was determined in the left cingulate gyrus from the same patient groups. In the head-injured group, choline acetyltransferase activity was consistently reduced in each cortical region compared to control subjects. The presence of a subdural haematoma and a prolonged survival period after head injury tended to be associated with lower choline acetyltransferase activity. In contrast to the marked reduction in choline acetyltransferase activity, nicotine receptor binding was unchanged in head-injured compared to control patients. Synaptophysin immunoreactivity in the cingulate gyrus was reduced by approximately 30% (p < 0.05) in the head-injured group compared to controls. Correlation of choline acetyltransferase activity with synaptophysin immunoreactivity indicated there is a deficit of cholinergic presynaptic terminals in postmortem human brain following head injury.
Adult↗
Axonal injury caused by focal cerebral ischemia in the rat.
The susceptibility of axons to blunt head injury is well established. However, axonal injury following cerebral ischemia has attracted less attention than damage in gray matter. We have employed immunocytochemical methods to assess the vulnerability of axons to cerebral ischemia in vivo. Immunocytochemistry was performed using antibodies to a synaptosomal-associated protein of 25 kDa (SNAP25), which is transported by fast anterograde transport; the 68-kDa neurofilament subunit (NF68kD); and microtubule-associated protein 5 (MAP5) on sections from rats subjected to 30 min and 1, 2, and 4 h of ischemia induced by permanent middle cerebral artery (MCA) occlusion. After 4 h of occlusion, there was increased SNAP25 immunoreactivity, which was bulbous in appearance, reminiscent of the axonal swellings that occur following blunt head injury. Increased SNAP25 immunoreactivity was present in circumscribed zones in the subcortical white matter and in the axonal tracts at the border of infarction, a pattern similar to that previously described for amyloid precursor protein. Although less marked, similar changes in immunoreactivity in axons were evident following 2 h of ischemia. MAP5 and NF68kD had striking changes in immunoreactivity in axonal tracts permeating the caudate nucleus within the MCA territory at 4 h. The appearance was roughened and disorganized compared with the smooth regular staining in axons within the nonischemic areas. Profiles reminiscent of axonal bulbs were evident in MAP5-stained sections. The changes seen with NF68kD and MAP5 were also evident at 2 h but were more subtle at 1 h. There were no changes in axonal immunoreactivity with SNAP25 or NF68kD at 30 min after MCA occlusion. Altered immunoreactivity following ischemia using SNAP25, MAP5, and NF68kD provides further evidence for the progressive breakdown of the axonal cytoskeleton following an ischemic insult. NF68kD and MAP5 appear to be sensitive markers of the structural disruption of the cytoskeleton, which precedes the subsequent accumulation of SNAP25 within the damaged axons. Axonal cytoskeletal breakdown and disruption of fast axonal transport, which are well-recognized features of traumatic brain injury, are also sequalae of an ischemic insult.
Animals↗
Rat and human hippocampal alpha5 subunit-containing gamma-aminobutyric AcidA receptors have alpha5 beta3 gamma2 pharmacological characteristics.
The gamma-aminobutyric acid (GABA)A receptor is a hetero-oligomer consisting of five subunits, the combination of which confers unique pharmacological properties to the receptor. To understand the physiological role of native GABAA receptors, it is critical to determine their subunit compositions. The pharmacological characteristics of human alpha5 beta3 gamma2 and alpha5beta3gamma3 GABAA receptors stably expressed in L(tk-) cells were characterized with the alpha5-selective ligand [3H]L-655,708 and compared with the pharmacological characteristics of [3H]L-655,708 binding sites from rat and human hippocampus. Saturation analyses revealed a 9-fold selective affinity of [3H]L-655,708 for alpha5 beta3 gamma2 receptors (Kd = 1.7 +/- 0.4 nM), compared with alpha5 beta3 gamma3 receptors (Kd = 15 +/- 3 nM). Rat and human hippocampal [3H]L-655,708 binding sites had affinities of 2.2 +/- 0.6 and 1.0 +/- 0.2 nM, respectively, comparable to the affinity of alpha5 beta3 gamma2 receptors. Pharmacological analysis of [3H]L-655,708 binding sites in rat and human hippocampi revealed a strong correlation with the affinities of seven benzodiazepine site ligands for alpha5 beta3 gamma2 but not alpha5 beta3 gamma3 receptors. Immunoprecipitation of [3H]L-655,708 binding sites from rat hippocampus with a gamma2-selective antibody yielded 19 +/- 4% of total benzodiazepine binding sites measured using [3H]Ro15-1788, whereas no specific binding was measured after immunoprecipitation with an anti-gamma3 antibody. Combinatorial immunoprecipitations of [3H]muscimol binding sites with anti-alpha5 and anti-gamma2 or anti-alpha5 and anti-gamma3 antibodies established the preferential expression of alpha5 gamma2 receptors, accounting for 22 +/- 2% of total rat hippocampal GABAA receptors. These observations provide pharmacological and structural evidence for the prevalence of alpha5 beta3 gamma2 GABAA receptors in rat hippocampus, despite the clustering of alpha5 and gamma3 loci on the same chromosome.
Adult↗
Clinical and economic outcome of mechanically ventilated patients in New York State during 1993: analysis of 10,473 cases under DRG 475.
STUDY OBJECTIVES: To examine and describe the relationship between age and disposition in patients undergoing mechanical ventilation. DESIGN: Retrospective analysis of a statewide database. SETTING: All acute-care hospitals in New York State. PATIENTS: All patients (n=10,473) aged > or = 18 years discharged from hospital during 1993 with a final diagnosis related group (DRG) coding of 475. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The final disposition, according to six codes (other acute-care facility, residential health-care facility, other health-care facility, home, home health-care services, and death) were examined for the whole population. Cost per case was assumed to equal the average statewide Medicaid rate. An inverse relationship between survival rate and age was observed and this resulted in an age-related increased cost per survivor. Also, survivors in older age groups have an increasing rate of hospital discharge to residential health-care facilities. CONCLUSION: Patients who undergo mechanical ventilation are expensive to care for. The older they are, the less satisfactory is the outcome both from clinical and economic perspectives.
Adolescent↗
Amyloid precursor protein accumulates in white matter at the margin of a focal ischaemic lesion.
Amyloid precursor protein (APP) is transported by fast anterograde axonal transport. Since disruption of this transport results in APP accumulation, APP has been proposed as a sensitive marker of axonal injury. In the present study, axonal injury in subcortical white matter and myelinated fibre tracts permeating the striatum, 24 h after permanent middle cerebral artery occlusion in the rat, has been examined by assessing the location and extent of APP immunoreactivity. Increased APP immunoreactivity was present in both areas. This was localised to a circumscribed zone immediately adjacent to the boundary of the ischaemic lesion in grey matter. The amount of APP immunoreactivity was associated with the volume of the ischaemic lesion in individual animals. Increased APP immunoreactivity in subcortical white matter and myelinated fibre tracts at the margin of the ischaemic zone may prove to be a valuable marker for assessing strategies to protect axons after an ischaemic insult.
Amyloid beta-Protein Precursor↗
High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy.
From the somewhat conflicting published data on apolipoprotein E (apoE) genotype in hemorrhage due to cerebral amyloid angiopathy (CAA), it is unclear whether apoE genotype influences the risk of CAA-related hemorrhage independently of its association with concomitant Alzheimer's disease (AD). We determined the apoE genotypes of 36 patients presenting with cerebral hemorrhage associated with histologically confirmed CAA. The frequency of apoE epsilon 2 was 0.25 and the frequency of apoE epsilon 4 was 0.18. Patients with CAA-related hemorrhage and concomitant AD pathology (CERAD criteria, n = 17) had a high apoE epsilon 4 frequency, close to that in AD cases without hemorrhage. Patients in whom CAA-related hemorrhage occurred in the absence of significant AD pathology (n = 13) had an apoE epsilon 4 frequency somewhat lower than non-AD controls without hemorrhage. However, in CAA-related hemorrhage, the apoE epsilon 2 frequency was high regardless of whether significant AD pathology was present. We conclude that whereas possession of apoE epsilon 2 may be a risk factor for cerebral hemorrhage due to CAA, apoE epsilon 4 is a risk factor for concomitant AD but not an independent risk factor for CAA-related hemorrhage.
Aged↗
The effect of postmortem delay on the distribution of microtubule-associated proteins tau, MAP2, and MAP5 in the rat.
Breakdown or disruption of the cytoskeleton has been implicated in the neurodegenerative processes of a variety of diseases, including Alzheimer disease (AD) and stroke. Studies of such diseases in the human involve the use of postmortem brain tissue. Postmortem delay may vary considerably from a few hours to a few days, and within this period, a degree of cytoskeletal breakdown may occur. It is therefore crucial to examine alterations occurring in the cytoskeleton as a result of postmortem delay and subtract these from those caused by the disease. In this study, the distribution of tau, MAP2, and MAP5 immunohistochemistry was examined following postmortem intervals of 0-72 h in the rat cerebral cortex, corpus callosum, caudate nucleus, and hippocampus. Each microtubule-associated protein (MAP) underwent unique changes that were dependent both on postmortem interval and the brain region examined. Following long postmortem delays, some of the changes in these proteins were similar to those seen in rodent models of cerebral ischemia. These results demonstrate that MAPs are not stable during postmortem delay in the rat. Therefore, caution must be exercised when interpreting changes in MAPs in human postmortem tissue, especially in cases where ischemic injury may be involved. Examination of control tissue carefully matched for postmortem delay is therefore essential to allow meaningful interpretation of cytoskeletal abnormalities in human neurodegenerative disease.
Animals↗
Changes of cytoskeletal protein immunostaining in myelinated fibre tracts after focal cerebral ischaemia in the rat.
Breakdown of the cytoskeleton has been proposed to be a central event in the evolution of ischaemic brain damage. Alterations in the immunostaining of cytoskeletal proteins, particularly microtubule-associated protein (MAP) 2, have been suggested to be sensitive markers of ischaemic damage in the somatodendritic compartment. However, axons are also subjected to the adverse conditions created by an ischaemic challenge, but MAP2 is not located in the axonal compartment. The purpose of the present study was to examine immunostaining of beta-tubulin, MAP1a and MAP5, all of which are located in axons as well as perikarya, specifically in myelinated fibre tracts in rats subjected to unilateral middle cerebral artery (MCA) occlusion. In sham-operated control rats immunostaining of all three antibodies in myelinated fibre tracts had a smooth, regular appearance. Two hours after MCA occlusion there were striking changes in the patterns of immunostaining of all three antibodies in myelinated fibre tracts within the MCA territory. These were particularly noticeable in beta-tubulin- and MAP5-stained sections where the pattern in white matter had a rough, globular appearance. This pattern was accentuated at 6 h after MCA occlusion and the presence of "bulb-like" profiles in white matter tracts was notable particularly in the MAP5-stained sections. Thus, the changes in the patterns of staining at 2 h after MCA occlusion may represent the early stages of axonal disconnection, and immunostaining of microtubular proteins may represent a sensitive method to assess ischaemically induced damage to myelinated fibre tracts.
Animals↗
Rapid alteration of tau in oligodendrocytes after focal ischemic injury in the rat: involvement of free radicals.
Glial inclusions containing the microtubule-associated protein tau are present in a variety of chronic neurodegenerative conditions. We now report a rapid and time-dependent increase of tau immunoreactivity within oligodendrocytes after focal cerebral ischemia in the rat. The number of tau positive oligodendrocytes in the ipsilateral subcortical white matter increased six- to eightfold by 40 minutes after permanent middle cerebral artery occlusion (MCAO). Tau was detected using antibodies that label both the N- and C-terminal of the protein, suggesting accumulation of full-length protein within these cells. Pretreatment with the spin trap agent alpha-phenyl-tert-butyl-nitrone (PBN)(100mg/kg) reduced the number of tau-positive oligodendrocytes by 55% in the subcortical white matter of the ischemic hemisphere compared with untreated animals at 40 minutes after MCAO. In contrast, pretreatment with glutamate receptor antagonists MK-801 (0.5 mg/kg) or 2,3-dihydroxy-6-nitro-7-sulpfamoyl-benzo(f)quinoxaline (NBQX) (2 x 30 mg/kg), failed to reduce the number of tau-positive oligodendrocytes after 40 minutes of ischemia. The results indicate that oligodendrocytes respond rapidly to an ischemic challenge and that free radical-mediated mechanisms are involved in the cascade leading to increased tau immunoreactivity.
Animals↗
Increased tau immunoreactivity in oligodendrocytes following human stroke and head injury.
Tau immunohistochemistry was performed on post-mortem brain tissue from patients who died following head injury or stroke and from neurologically normal controls. Tau-positive oligodendrocytes were detected with three different tau antibodies in head injured or stroke patients, but not in control cases. Tau-positive oligodendrocytes were detected 2 h following head injury indicating that accumulation of tau may be an acute response of these cells to brain injury. The mechanisms underlying accumulation of tau in oligodendrocytes after acute brain injury may be similar to those which occur in chronic neurodegenerative conditions such as progressive supranuclear palsy (PSP) and multi-system atrophy (MSA).
Adult↗
Alteration in brain presenilin 1 mRNA expression in early onset familial Alzheimer's disease.
The expression of the presenilin 1 (PS-1) gene has been investigated by in situ hybridization in early onset familial Alzheimer's disease (FAD), late onset Alzheimer's disease (AD) and normal control brain. Mutations in this gene are responsible for chromosome 14-linked FAD. We have found that presenilin 1 mRNA is present throughout the human brain with a distribution consistent with both a glial and neuronal localization. The in situ hybridization pattern was similar for the controls, the early onset FAD cases and the late onset AD cases. However, one of the two forms of the mRNA for PS-1, the long form (which contains a sequence encoding a four amino acid (VRSQ) insert at its 5' end) was significantly reduced in early onset FAD brain compared with late onset AD. We suggest that this long transcript may alter the normal pathway for processing of amyloid precursor protein, the protein which appears to be central in the pathogenesis of AD.
Adult↗
Intracortical perfusion of glutamate in vivo induces alterations of tau and microtubule-associated protein 2 immunoreactivity in the rat.
Modifications of microtubule-associated proteins (MAP) have been reported in both acute and chronic degenerative conditions, such as cerebral ischaemia and Alzheimer's disease, and may be associated with cytoskeletal breakdown. Glutamate excitotoxicity has been implicated in the pathogenesis of both of these conditions and has been shown in some in vitro studies to induce changes in tau similar to those occurring in Alzheimer's disease. This study examines the effects of high extracellular glutamate concentrations on the distribution of tau and MAP2 in vivo in order to determine whether glutamate induces similar changes in tau to those previously reported in vitro in the intact, adult central nervous system. Monosodium glutamate was perfused into the rat parietal cortex for 90 min using in vivo microdialysis and at 4 h after the start of perfusion the distribution of tau and MAP2 was determined by immunohistochemistry. At the core of the glutamate-induced lesion tau immunostaining, as detected with the Tau 1 antibody, was decreased in axons and increased within perikarya compared to controls. Increased immunostaining was not apparent with polyclonal antibodies raised against full-length tau or towards the N or C termini of the protein. In contrast, increased tau immunoreactivity was detected, with all the antibodies used in this study, within oligodendrocytes following either glutamate or sodium chloride perfusion. MAP2 immunoreactivity was increased within perikarya at the core of the glutamate-induced lesion, while dendritic immunoreactivity was reduced. These results suggest that glutamate excitotoxicity in vivo may not be involved in neurofibrillary tangle formation but may be important in the progression of cytoskeletal pathology following cerebral ischaemia.
Animals↗
The neuronal cytoskeleton: an insight for neurosurgeons.
The cytoskeleton is important in the structure and function of the neuron. Disruption of the cytoskeletal proteins occurs in a variety of forms of acute brain injury including cerebral ischaemia and diffuse anonal injury. The final common pathway mediating neuronal cell death involves loss of the integrity of the cytoskeleton and these disturbances may have a key role in the progression of events following acute brain injury. This review aims to provide an insight into the neuronal cytoskeleton in the normal state and in disorders encountered in neurosurgical practice.
Axons↗
Depletion of choline acetyltransferase activity but preservation of M1 and M2 muscarinic receptor binding sites in temporal cortex following head injury: a preliminary human postmortem study.
Abnormalities of cholinergic neurotransmission have been implicated in the memory deficits that result from head injury on the basis of results obtained from experimental animal models and cholinergic agonist treatment in head-injured survivors. The purpose of the present study was to make a preliminary investigation of pre- and postsynaptic markers of cholinergic transmission in human postmortem brain from patients who died as a result of head injury and age matched controls. Choline acetyltransferase activity, M1 and M2 receptor binding sites were assayed in the inferior temporal gyrus from 7 head-injured patients and 7 controls. The mean value of choline acetyltransferase activity was reduced by approximately 50% in the head-injured group compared to the control, although in 2 head-injured cases enzyme activity was similar to that of controls. In contrast to the reduction in choline acetyltransferase activity, there was no difference between the head-injured and control groups in the levels of either M1 or M2 receptor binding. These preliminary results indicate that there is a significant presynaptic abnormality of cholinergic neurotransmission in postmortem human brain following head injury but that muscarinic receptor binding sites are unaltered.
Aged↗
Tau protein is altered by focal cerebral ischaemia in the rat: an immunohistochemical and immunoblotting study.
Breakdown of the cytoskeleton may be involved in the evolution of ischaemic brain damage and alterations in microtubule-associated proteins may play an important role in this process. In the present study, tau, a microtubule-associated protein predominantly located in axons, was examined after 2 or 6 h of focal cerebral ischaemia in the rat. Immunohistochemistry revealed increased Tau1 staining in the neuropil, some perikarya and in glial cells throughout the dorsolateral caudate nucleus and ventrolateral neocortex in the ipsilateral hemisphere at both 2 and 6 h after occlusion of the middle cerebral artery. Contrastingly, immunostaining of another tau antibody, TP70, was unchanged in the neuropil, but was increased specifically in glial cells in these regions. Immunoblotting revealed the presence of additional tau bands in tissue extracts of the caudate nucleus and ventrolateral neocortex ipsilateral to the occluded middle cerebral artery as detected by both tau antibodies after either 2 or 6 h. The results suggest that tau is dephosphorylated and/or degraded in axons and some neuronal perikarya in response to focal cerebral ischaemia. In contrast to the response in neurons, increased immunoreactivity of both tau antibodies in glial cells indicates a differential response of neuronal and glial tau to focal cerebral ischaemia.
Animals↗