Autoxidation of amyloid precursor protein and formation of reactive oxygen species.
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Amyloid beta-Protein Precursor↗
Biomedical subjects
L Hesse
Publications and source records attributed to L Hesse.
[Etiology of corneal opacities after plasminogen activator-induced fibrinolysis of the anterior chamber].
BACKGROUND: After treatment of anterior chamber fibrinous reactions by tissue plasminogen activator (TPA), irreversible corneal opacifications (calcium phosphate) have been observed. To understand the mechanism of these opacifications an animal model was developed. MATERIAL AND METHODS: In rabbits the lens was removed by phacoemulsification. The surgical procedure was completed by an injection of TPA (25 micrograms) into the anterior chamber. In a second group TPA fibrinolysis (25 micrograms) was induced 10 min after injection of autologous blood. In a third group 25 micrograms of TPA was injected into the anterior chamber after circumscribed mechanical lesion of the corneal endothelium. Changes in corneal structure and transparency were determined by biomicroscopy and histopathologic examination. RESULTS: After lensectomy or mechanically induced lesion of the corneal endothelium followed by TPA injection, sharply defined interpalpebral corneal opacifications developed within 3 to 8 days. Histologically, deposits were located in Bowman's membrane and in superficial stromal layers. No opacifications developed after fibrinolysis of an intracameral clot. CONCLUSIONS: Corneal opacifications as seen in humans after fibrinolysis by intracameral injection of TPA requires a temporary disturbance of the endothelial function. This allows phosphate (buffer of TPA) and calcium (aqueous humour) to distribute within the corneal stroma. Then there are insoluble calcium phosphate precipitates because of recovery of the endothelial function and dehydration of the cornea.
Animals↗
Management of acute submacular hemorrhage using recombinant tissue plasminogen activator and gas.
PURPOSE: To assess the effects of intravitreal injection of recombinant tissue plasminogen activator (rTPA) and gas on submacular hemorrhage in age-related macular degeneration (ARMD). METHODS: Eleven consecutive patients (11 eyes) with subretinal hemorrhage due to ARMD involving the fovea with elevation of the neurosensory retina were included in this study. Subretinal hemorrhage occured 12 h to 14 days before onset of therapy. Injection of rTPA through the pars plana in a dose of 50 or 100 microg was performed. Gas instillation (0.2-0.4 ml) followed rTPA injection, either immediately after injection (7 patients) or during the following day (4 patients). RESULTS: After intravitreal injection of rTPA, subretinal clots were totally or partially liquefied when treatment started up to 3 days after onset of bleeding. In all patients treated with 100 microg rTPA a large exudative retinal detachment of the inferior retina resulted, which reabsorbed spontaneously within 2 weeks. After reattachment of the exudative retinal detachment hyperpigmentation of the retinal pigment epithelium was noted. Temporary opacification of the vitreous was observed between the 2nd and 7th postoperative day in 5 eyes (45.5%). Postoperative visual acuity increased in 5 patients (45.5%). CONCLUSION: Intravitreal application of rTPA followed by gas injection is a sufficient and convenient technique for effective removal of freshly formed submacular hemorrhage. Removal is mediated through combined enzymatic (rTPA) and mechanical (gas) effects. This technique offers a quick recovery of vision in eyes with less severe ARMD.
Acute Disease↗
Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein.
Amyloid precursor protein (APP) plays a central role in Alzheimer disease. A proteolytic-breakdown product of APP, called beta-amyloid, is a major component of the diffuse and fibrillar deposits found in Alzheimer diseased brains. The normal physiological role of APP remains largely unknown despite much work. A knowledge of its function will not only provide insights into the genesis of the disease but may also prove vital in the development of an effective therapy. Here we describe the 1.8 A resolution crystal structure of the N-terminal, heparin-binding domain of APP (residues 28-123), which is responsible, among other things, for stimulation of neurite outgrowth. The structure reveals a highly charged basic surface that may interact with glycosaminoglycans in the brain and an abutting hydrophobic surface that is proposed to play an important functional role such as dimerization or ligand binding. Structural similarities with cysteine-rich growth factors, taken together with its known growth-promoting properties, suggests the APP N-terminal domain could function as a growth factor in vivo.
Alzheimer Disease↗
[Enzymatically induced posterior vitreous detachment in proliferative diabetic vitreoretinopathy].
BACKGROUND: Complete detachment of the posterior vitreous cortex is an important aim in the treatment of proliferative diabetic vitreoretinopathy (PDVR). Today a posterior vitreous detachment (PVD) can only be achieved during vitrectomy. A randomized pilot study was started to evaluate wether intravitreally injected TPA is sufficient to induce a PVD in diabetic eyes. PATIENTS AND METHODS: Eight weeks prior to vitrectomy because of proliferative diabetic vitreoretinopathy (non-clearing haemorrhage, fibrovascular proliferations) 20 eyes which had an attached vitreous received a cryopexy of the peripheral retina. In 11 eyes that had been selected at random 10 micrograms of recombinant tissue plasminogen activator were injected midvitreally 24 hrs later. A newly formed PVD was assessed by means of biomicroscopy or ultrasound. RESULTS: A newly formed partial (n = 3) or complete (n = 7) PVD was found in 10 of 11 TPA-treated eyes versus one partial detached vitreous in the control group. In 3 younger patients PVD developed exclusively after TPA-injection. We did not observe severe changes of the ERG, decrease of visual acuity, severe new vitreous haemorrhages or opacities of the lens. In 3 eyes (2 eyes of the control group) a circumscribed retinal detachment developed during the follow-up period. CONCLUSIONS: The described technique can be used in diabetics without severe side effects. It facilitates the removal of the vitreous cortex and may be a valuable adjunct to the surgical management of PDVR. Unlike other proteases TPA is available for clinical use through recombinant DNA technology which allows standardized enzymatic activities, steril and non-infectious conditions.
Adult↗
Stress-induced rat intestinal mast cell intragranular activation and inhibitory effect of sulfated proteoglycans.
Cyclic vomiting syndrome is characterized by sudden episodes of vomiting and abdominal pain. It occurs primarily in children, is exacerbated by stress, and is often considered a migraine equivalent. Migraines have been linked to mast cells, which are often found close to neurons where they are activated by neuropeptides. We investigated the ultrastructural appearance of rat ileal brush border and mast cells following acute stress by immobilization. The effect of sulfated proteoglycans heparin and chondroitin sulfate was also tested on mast cell histamine secretion. Ileal brush border appeared intact in control animals, but was shorter and exhibited intercellular gaps after 30 min of acute immobilization stress. Mast cell activation in control rats was minimal, while stress induced obvious signs of activation as judged from disappearance of secretory granule electron dense contents. However, these intragranular changes were not accompanied by typical degranulation through exocytosis. Treatment of purified homogeneic rat peritoneal mast cells with 10(-4) M heparin or chondroitin sulfate 30 min prior to stimulation with 0.5 microg/ml compound 48/80 decreased histamine release by over 70% and 50% (P < 0.05), respectively. These results suggest the possible usefulness of chondroitin sulfate in conditions such as cyclic vomiting syndrome.
Animals↗
Survival of cultured neurons from amyloid precursor protein knock-out mice against Alzheimer's amyloid-beta toxicity and oxidative stress.
Studies on the amyloid precursor protein (APP) have suggested that it may be neuroprotective against amyloid-beta (Abeta) toxicity and oxidative stress. However, these findings have been obtained from either transfection of cell lines and mice that overexpress human APP isoforms or pretreatment of APP-expressing primary neurons with exogenous soluble APP. The neuroprotective role of endogenously expressed APP in neurons exposed to Abeta or oxidative stress has not been determined. This was investigated using primary cortical and cerebellar neuronal cultures established from APP knock-out (APP-/-) and wild-type (APP+/+) mice. Differences in susceptibility to Abeta toxicity or oxidative stress were not found between APP-/- and APP+/+ neurons. This observation may reflect the expression of the amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2) molecules and supports the theory that APP and the APLPs may have similar functional activities. Increased expression of cell-associated APLP2, but not APLP1, was detected in Abeta-treated APP-/- and APP+/+ cultures but not in H2O2-treated cultures. This suggests that the Abeta toxicity pathway differs from other general forms of oxidative stress. These findings show that Abeta toxicity does not require an interaction of the Abeta peptide with the parental molecule (APP) and is therefore distinct from prion protein neurotoxicity that is dependent on the expression of the parental cellular prion protein.
Alzheimer Disease↗
Copper-binding amyloid precursor protein undergoes a site-specific fragmentation in the reduction of hydrogen peroxide.
The extracellular domain of transmembrane Abeta amyloid precursor protein (APP) has a Cu(II) reducing activity upon Cu(II) binding associated with the formation of a new disulfide bridge. The complete assignment of the disulfide bond revealed the involvement of cysteines 144 and 158 around copper-binding histidine residues. The vulnerability of APP-Cu(I) complexes to reactive oxygen species was elaborated as a site-specific and random fragmentation of APP in a time-dependent manner and at low concentrations of H2O2. Analysis of the specific reaction revealed the generation of C-terminal polypeptides, containing the Abeta domain. APP catalyzed the reduction of H2O2 and oxidation of Cu(I) to Cu(II) in a "peroxidative" reaction in vitro. The resulting bound copper-hydroxyl radical intermediate [APP-Cu(II)(.OH)] then likely participated in a Fenton type of reaction with radical formation as a prerequisite for protein degradation. Evidence from two observations suggests that the reaction takes place in two phases. Bathocuproine, a trapping agent for Cu(I), abolished the initial fragmentation, and chelation of Cu(II) by DTPA (diethylenetriaminepentaacetic acid) interrupted the reaction cascade induced by H2O2 at later stages. Consequently, the results suggest that a cytotoxic gain-of-function of APP-Cu(I) complexes might result in a perturbation of free radical homeostasis. What significance such a perturbation may have for the pathogenesis of Alzheimer's disease remains to be determined.
Amino Acid Sequence↗
Inhibition of platelet activation by the Alzheimer's disease amyloid precursor protein.
The amyloid precursor protein (APP) of Alzheimer's disease is abundantly expressed in the platelet alpha-granule where its role remains unclear. This study describes a novel function for APP in regulating human platelet activation. Preincubation of platelet-rich plasma with recombinant secreted APP (sAPP) isoforms dose-dependently inhibited platelet aggregation and secretion induced by ADP or adrenaline. Similarly, sAPP potently inhibited low-dose thrombin-induced activation in washed platelet suspensions, indicating that the activity does not require plasma cofactors. There were no functional differences between sAPP forms with or without the Kunitz protease inhibitor domain or derived from either alpha- or beta-secretase cleavage. In fact, the N-terminal cysteine-rich region of APP (residues 18-194) was as effective as the entire sAPP region in the inhibition of platelet activation. The inhibitory activity of sAPP correlated with a significant reduction in the agonist-induced production of the arachidonic acid (AA) metabolites thromboxane B2 and prostaglandin E2. However, sAPP did not affect AA-induced platelet aggregation or secretion, indicating the enzymatic conversion of AA was not inhibited. The addition of a threshold dose of AA reversed the sAPP-inhibition of agonist-induced platelet activation. This suggests that sAPP decreases the availability of free AA, although the mechanism is not yet known. These data provide evidence that the release of sAPP upon platelet degranulation may result in negative feedback regulation during platelet activation.
Adenosine Diphosphate↗
Human amyloid precursor-like protein 1--cDNA cloning, ectopic expression in COS-7 cells and identification of soluble forms in the cerebrospinal fluid.
Amyloid precursor-like protein 1 (APLP1) represents an integral membrane type 1 protein of unknown function which was originally cloned from a mouse cDNA library on the basis of sequence similarity with the Alzheimer's amyloid precursor protein (APP). Here we report on the molecular cloning and expression of the human APLP1 (hAPLP1). hAPLP1 consists of 650 amino acids, displays 89% identity on the amino acid level to its mouse homologue and has a calculated molecular mass of 72 kDa. hAPLP1 synthesized in a cell-free system displays an apparent molecular mass of approximately 80 kDa in SDS-containing gels and becomes N-glycosylated when the in vitro translation is performed in the presence of microsomes. The hAPLP1 cDNA was also expressed ectopically in COS-7 cells and the protein expression was analyzed by immunoprecipitation and western blotting. We have demonstrated that hAPLP1 represents a novel glycoprotein which carries both N- and O-linked glycans. Moreover, hAPLP1 undergoes limited proteolysis which results in the secretion of the carboxy-terminal truncated molecule into the cells conditioned medium. Examination of cells transfected with hAPLP1 cDNA by confocal laser microscopy reveals an intense perinuclear and Golgi staining, a pattern resembling the subcellular distribution of APP. Using a novel hAPLP1-specific antiserum, we identified soluble hAPLP1 in the human cerebrospinal fluid, which suggests that secretion of hAPLP1 from brain cells also takes place in vivo.
Amino Acid Sequence↗
Reactive oxygen species and Alzheimer's disease.
Although a consensus that Alzheimer's disease (AD) is a single disease has not been reached yet, the involvement of the amyloid precursor protein (APP) and betaA4 (A beta) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of betaA4 in cell cultures, and the findings that aggregation of betaA4 can be induced by metal-catalyzed oxidation and that free oxygen radicals may be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS may be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.
Aging↗
[Retinal detachment in Ehlers-Danlos syndrome. Treatment by pars plana vitrectomy].
UNLABELLED: Ehlers-Danlos syndrome (EDS) is an hereditary connective tissue disorder caused by defective collagen synthesis, the main features being hyperelasticity and vulnerability of the skin, recurrent bleeding from fragile blood vessels, and secondary deformities of the joints. Ocular involvement is a rare occurrence, e.g., corneal and scleral rupture from minor blunt injury, lens displacement, rhegmatogenous retinal detachment. To date, few reports exist concerning the treatment of retinal detachment in Ehlers-Danlos syndrome, all of them dealing exclusively with conventional scleral buckling surgery. PATIENT AND METHODS: We report on a 47-year-old male patient suffering from EDS type VI (so-called ocular type, lysine-hydroxylase deficiency). He presented with rhegmatogenous retinal detachment in his only eye. A scleral buckling procedure was not feasible because of marked scleral atrophy. A three-port vitrectomy was therefore carried out. RESULTS: During the operation, pronounced choroidal detachment and bleeding developed, subsiding within weeks postoperatively. Closure of the sclerotomies was difficult due to scleral thinning. Two revitrectomies were necessary because anterior PVR with traction retinal detachment occurred. The last revitrectomy was performed 18 months ago, and the retina has been completely reattached under 5000 cs silicone oil since then. Visual acuity is 0.1. CONCLUSION: Primary vitrectomy permits successful treatment of retinal detachment in EDS patients if a buckling procedure cannot be performed because of scleral atrophy. However, serious complications may occur. Surgical procedures other than primary vitrectomy should therefore always be carefully considered, e.g., pneumatic retinopexy, temporary balloon, dura patch with episcleral pocket.
Ehlers-Danlos Syndrome↗
[Reduction of cataract by plasma etching of intraocular lenses. An animal experiment study].
BACKGROUND: We studied if a modification of the silicon intraocular lens (IOL) by plasma etching is able to promote a bonding of the IOL surface and the capsular bag which might inhibit proliferation and migration of lens epithelial cells. METHODS: Silicon-disc lenses (90D, Adatomed), as disposable for regular cataract surgery, were used. Their haptic surface was etched via the use of a SO2 plasma, leaving the optic unmodified. The experiments were done on dwarf rabbits to allow for tight apposition of IOL and bag. Nine rabbits underwent extracapsular lensectomy using propofol anaesthesia and phaco/clear cornea surgical technique. Six eyes each received either no, a regular or a modified IOL. After 11 weeks the eyes were enucleated. Capsular bag and IOL were digitized using a flatbed scanner with transparency adapter. The data obtained were calibrated against a densitometric standard. The densities of the various specimen were analyzed quantitatively using self designed software. RESULTS: In aphacic eyes no significant posterior capsule opacification (PCO) was detectable. In the same time-span the regular IOL had developed a dense, heterogenous PCO. The plasma-treated IOL showed, especially in the central areas, a significant reduction of PCO as compared to untreated IOL. CONCLUSION: The reduction of PCO could not be explained by adhesion of the IOL surface and the capsular bag, which would impair migration of lens epithelial cells and thereby PCO. Likewise, lower PCO may be related to improved hydrophilic properties of the surface-modified IOL.
Animals↗
Blood transfusion. Iron load and retinopathy of prematurity.
UNLABELLED: To study the relationship between blood transfusion, iron load and retinopathy of prematurity (ROP), we performed a prospective observational cohort study in a level III neonatal intensive care unit. During a 24-month period, data on the volume of blood transfused during the first 6 weeks of life and on the incidence of ROP were collected in all surviving very low birth weight infants (n = 114; median birth weight 1130 g. range 520-1500 g). Associations between these data and values for serum iron, transferrin and ferritin measured at weekly intervals were analysed in a nested case-control design by logistic regression. There was a significant association between the volume of blood transfused and the incidence of ROP. After adjustment for gestational age at birth, duration of oxygen therapy (FiO2 > 0.3) and duration of mechanical ventilation, the relative risk of developing ROP was 6.4 (95% CI 1.2-33.4) for infants who had received 16-45 ml/kg, and 12.3 (1.6-92.5) for those who had received more than 45 ml/kg of blood (reference, 0-15 ml/kg). In contrast, there was no independent relationship between ROP and any of the parameters on iron metabolism analysed. CONCLUSION: This study confirms the role of blood transfusions as an independent risk factor for ROP. This relationship, however, does not appear to be mediated via an increased iron load.
Case-Control Studies↗
[Acute glaucoma caused by massive subretinal hemorrhage in age-related macular degeneration and disordered thrombocyte function].
BACKGROUND: Hemorrhages from subretinal neovascularizations in age-related macular degeneration are not uncommon, but usually limited to the posterior pole. A therapy-resistant angle closure glaucoma following displacement of the lens-iris diaphragm due to massive choroidal and subretinal hemorrhages has rarely been reported. CASE REPORT: A 72-year-old female patient was first seen in September 1993 because of decreased vision in the right eye. An age related macular degeneration with an extended untreatable neovascularisation membrane was diagnosed. One year later sudden pain attacks were initiated by secondary angle closure glaucoma, caused by a massive choroidal and subretinal bleeding. At first the IOP could be regulated by drug therapy, however, recurring hemorrhages led to continuously elevated IOP. The reason for the recurrent massive hemorrhages was found to be a disorder of the platelet function. Since the IOP (50-80 mm Hg) could not be controlled any further, we decided to perform a sclerotomy in an attempt to drain the blood. Within one day another bleeding occurred and again led to an increase in IOP. Finally, the patient agreed to have the eye enucleated. CONCLUSION: In case of massive hemorrhages in age related macular degeneration a haematological systemic disorder must be included in the diagnostic considerations. If the intraocular pressure can not be lowered neither medically nor surgically, enucleation can not be avoided.
Acetaminophen↗
Silicone oil for recurrent vitreous hemorrhage in previously vitrectomized diabetic eyes.
AIMS: To investigate the clinical course of vitrectomized patients with recurrent diabetic vitreous hemorrhage who were treated by revitrectomy with silicone oil (SO) as a hemostyptic tamponade. PATIENTS AND METHODS: Fifteen patients with recurrent vitreous hemorrhage due to proliferative diabetic vitreoretinopathy were included in this retrospective study. All eyes had had at least one vitrectomy prior to use of SO and the retina was completely attached at any time before revitrectomy with SO instillation. Thirteen patients had a blind fellow eye. There were 6 males and 9 females (mean age 62.7 years, range 45-76 years). The mean duration of SO tamponade was 25.8 months (range 9-35 months). The average follow-up period was 30.4 months (range 20-48 months). RESULTS: Ten out of 15 eyes (66.6%) improved postoperatively, 9 eyes had a visual acuity of > or = 0.02 at the latest follow-up visit. Secondary glaucoma occurred in 4 eyes, leading to phthisis in 1 eye. All 5 phakic eyes developed a cataract. CONCLUSION: A revitrectomy combined with a long-term hemostyptic SO tamponade offers a chance for restoration of useful visual acuity in diabetic eyes with persistent vitreous-hemorrhage that fails to subside after cryocoagulation and vitrectomy without tamponade. Because of possible visual loss from secondary glaucoma related to intraocular SO this treatment should mainly be considered in patients with a blind fellow eye.
Aged↗
Histopathological and immunohistochemical findings associated with a null mutation in the Norrie disease gene.
PURPOSE: To determine the clinical, histopathological, and immunohistochemical ocular changes associated with a null mutation in the Norrie disease protein (NDP) gene. METHODS: Tissue from a six-month-old boy with bilateral retrolental membranes and retinal detachment was obtained during vitreoretinal surgery. Histological sections were stained immunohistochemically with specific antibodies. No eye diseases with severe visual impairment or blindness were reported in the parents and their families. The NDP gene was analyzed by standard molecular genetic methods. RESULTS: A severe reduction in the number of retinal ganglion cells and a largely disarranged and hypoplastic inner nuclear layer were visible in the tissue specimen. Areas of the tissue with advanced pathology displayed massive fibrovascular proliferation in the vitreous cavity. Shrinkage and traction resulted in folding and detachment of the outer retina. Immunohistochemical reactivity for MIB(1) antigen demonstrated many proliferating cells in the vitreous, but no proliferative activity in the neuroretina. Retinal neurons showed a high grade of differentiation and expressed uniformly neuron-specific enolase and synaptophysin. A 1-base pair insertion (544/545insA) in the NDP gene was found in the affected boy. This mutation predicts a 'functional null-allele' due to a shift in the reading frame and, thus, a premature termination of mRNA translation after 55 instead of 133 amino acids. CONCLUSIONS: Loss of function of the NDP gene causes marked hypoplasia of the inner retinal cell layers and fibrovascular proliferation in the vitreous cavity, leading to retinal folding and detachment. The NDP therefore seems to play a critical role in terminal differentiation of the inner retinal cell layers and establishment and maintaining of anti-proliferative cellular interactions in the vitreous.
Antigens, CD↗
[Tissue-type plasminogen activator. An enzyme with multiple uses in ophthalmology].
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Eye Diseases↗