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Biomedical subjects

G Perry

Publications and source records attributed to G Perry.

At least 181 records · Page 10Linked to original sources
PubMed1993

Barrier properties of testis microvessels.

The blood-testis barrier is believed to be constituted by tight junctions between Sertoli cells in seminiferous tubules and possibly by myoid cells that encircle these tubules. We now show that testis microvessels are endowed with several markers of barrier properties of brain microvessels, such as the glucose transporter, P-glycoprotein, and gamma-glutamyl transpeptidase. Quantitative EM studies show that the endothelium in testis, as in brain, is continuous and has long junctional profiles and few vesicles. However, a small proportion of testis capillaries have expansions in their junctional clefts suggestive of patent paracellular channels, which may explain their higher permeability. Because barrier features are thought to be induced and/or maintained in brain microvessels by astrocytes, we assessed whether astrocyte-like cells exist in the testis. We found that the intertubular Leydig cells, adjacent to microvessels, express the astrocyte markers: glial fibrillary acidic protein, glutamine synthetase, and S-100 protein. We suggest that the testis endothelium contributes to the blood-testis barrier and that these endothelial barrier features are influenced by Leydig cells. We believe that the endothelial and the epithelial (Sertoli) components of the blood-testis barrier are "in series" and complement each other in achieving a stable milieu for spermatogenesis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Abnormal accumulation of phospholipase C-delta in filamentous inclusions of human neurodegenerative diseases.

We have previously demonstrated that an antibody to phosphoinositide-specific phospholipase C (PLC) isozyme, PLC-delta, intensely stained neurofibrillary tangles (NFT) in the brain tissue of Alzheimer's disease (AD). This study was performed to determine if abnormal PLC-delta accumulation might be present in the filamentous inclusions of other neurodegenerative diseases. We found that the anti-PLC-delta antibody stained neuronal inclusions of Pick's disease, progressive supranuclear palsy and diffuse Lewy body disease while the inclusions of idiopathic Parkinson's disease lacked PLC-delta accumulation. These results suggest a possible role for PLC-delta interaction in the formation of intraneuronal filamentous inclusions in human neurodegenerative diseases.

Aged↗
PubMed1993

Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease.

In cerebral amyloid angiopathy, the amyloid-beta (A beta) deposits lie primarily in the tunica media suggesting that smooth muscle cells play an important role in A beta deposition. To define this role, we conducted an immunocytochemical study of brain tissue from cases of Alzheimer disease with extensive cerebral amyloid angiopathy and cerebral hemorrhage. Antibodies specific to recombinant beta protein precursor (beta PP) and synthetic peptides homologous to various beta PP sequences from residue 18 to 689 of beta PP695 were used. Antibodies to actin, tropomyosin, alpha-actinin or desmin were used to label muscle cells. Antibodies to A beta sequences intensely recognized the extracellular amyloid deposit. Antibodies raised against beta PP sequences other than the A beta domain recognized smooth muscle cells. beta PP-immunoreactivity was reduced in regions of A beta deposits, since no muscle cells were recognized by cytoskeletal markers or observed ultrastructurally. In order to assess why A beta is deposited in the tunica media, we used biotin-labelled beta PP to determine if beta PP can be locally retained. We found beta PP bound to the tunica media of vessels but not other brain elements. These findings suggest A beta in blood vessels derives from degenerating beta PP-containing smooth muscle cells.

Actinin↗
PubMed1993

Aberrant phosphoinositide metabolism in Alzheimer's disease.

Since phosphoinositide-specific phospholipase C (PLC) is one of the key molecules in signal transduction, its involvement was assessed in Alzheimer's disease (AD). The phosphatidyl-inositol (PI)-specific PLC activity in the Alzheimer cytosolic and particulate fractions was not significantly different from that in the control fractions. The PI-specific PLC activity as a function of the free Ca2+ concentration was also similar between control and Alzheimer brains. These results suggest that the PI-specific PLC activity is not altered in AD. Immunostaining of a specific antibody against the PLC isozyme, PLC-delta, demonstrated that this enzyme was abnormally accumulated in neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores, and neuropil threads in AD brains. Western blot analysis confirmed that PLC-delta was concentrated in the paired helical filament (PHF)-rich fraction of AD brains. PLC-delta marked the same neurons containing tau immunoreactivity and yet tau and PLC-delta often marked different structures within the same neuron, with tau more clearly on NFT and PLC-delta covering it superficially. The double stain with PLC-delta and basic fibroblast growth factor (bFGF) binding suggest that PLC-delta is an intracellular marker, showing little overlap with bFGF binding, an extracellular marker. All of this was consistent with the electron microscopy, with PLC-delta being NFT associated. Antibodies to other PLC isozymes did not produce positive immunostaining of these pathologic structures. Moreover, diffuse and amorphous deposits of PLC-delta were found to precede the accumulation of fibrillary deposits. These results suggest that PLC-delta accumulation plays a possible role in the formation of intraneuronal inclusions in AD.

Alzheimer Disease↗
PubMed1993

The amyloid precursor protein in ischemic brain injury and chronic hypoperfusion.

We studied changes in the spatial and temporal distribution of the beta amyloid precursor protein (APP) of Alzheimer's disease (AD) in experimental ischemic brain injury. Rats with repeated reversible occlusions of one middle cerebral artery showed striking APP reactivity in astrocytic processes in perifocal regions and adjacent white matter. APP reactive dystrophic axons and neurons were also evident in the cortex and hippocampus ipsilateral to the MCA occlusion. Such changes were similarly apparent in animals subjected to partial forebrain ischemia induced by bilateral occlusion of the carotid arteries. Our studies suggest that focal ischemic insults or chronic hypoperfusion leads to increased accumulation or induction of APP in surviving cellular elements that may relate to the processes involved in beta amyloid deposition in AD.

Amyloid beta-Protein Precursor↗
PubMed1993

Alpha 1-trypsin immunoreactivity in Alzheimer disease.

This study is the initial demonstration of trypsin-like immunoreactivity within the human CNS. Using two monoclonal antibodies to alpha 1-trypsin, we found trypsin-like immunoreactivity associated with the senile plaques of Alzheimer disease. Immunoblots prepared from homogenized Alzheimer and control cortex showed increased amounts of the 24,000Da alpha 1-trypsin species in diseased compared to control tissue. We suggest an alteration in alpha 1-trypsin protease regulation could be important in the formation of senile plaques and the pathogenesis of Alzheimer disease.

Aged↗
PubMed1993

Ontogeny of the erythroid/HepG2-type glucose transporter (GLUT-1) in the rat nervous system.

Central nervous system (CNS) microvessels of adult mammals have an unusually high density of the facilitative glucose transporter GLUT-1. Most systemic microvessels and those of the brain's circumventricular organs, which lack 'barrier' properties, do not express a high density of GLUT-1. Thus, a high GLUT-1 density is a marker of adult brain endothelium. To determine the stage at which CNS microvessels acquire GLUT-1, we studied by immunocytochemistry GLUT-1 ontogeny in the rat CNS from embryonic day (E) 11 to senescence. At E11, before blood vessels invaded the neuroectodermal tube, GLUT-1 immunoreactivity was already evident in the perineural plexus of vessels and in most of the vascular endothelium of the embryo. GLUT-1 immunoreactivity was also evident in the neuroectoderm. The neuroectoderm gradually lost GLUT-1 expression, and at about E16, GLUT-1 immunoreactivity was no longer detectable in most of the neuroectodermal epithelium, while CNS microvessels had increased their GLUT-1 immunoreactivity. By birth, GLUT-1 immunoreactivity in the CNS was restricted to the endothelium, the epithelium (but not the endothelium) of the choroid plexus, and tanycytes. This cellular distribution of GLUT-1 did not change much between birth and senescence despite considerable postnatal brain development and the increased brain capillary density. Our results suggest that while a CNS factor(s) may not have a role in the induction of the high expression of GLUT-1 in CNS endothelium, such a factor(s) is probably important in maintaining the high level of GLUT-1 in these endothelia.

Aging↗
PubMed1993

Rimmed vacuoles of inclusion body myositis and oculopharyngeal muscular dystrophy contain amyloid precursor protein and lysosomal markers.

Rimmed vacuoles are small areas of focal destruction of muscle fibres, found in inclusion body myositis, oculopharyngeal muscular dystrophy and other muscle disorders. They are known to contain amyloid proteins, probably of beta-amyloid type. We examined rimmed vacuoles immunohistochemically in 12 patients with inclusion body myositis and two patients with oculopharyngeal muscular dystrophy with antibodies to beta-amyloid precursor protein and cathepsin B and D. We found evidence for the presence of all these markers in rimmed vacuoles. These results confirm the presence of beta-amyloid in rimmed vacuoles, and provide additional support for the hypotheses that rimmed vacuoles are of lysosomal origin and that lysosomes are probably important in the metabolism of amyloid precursor protein.

Aged↗
PubMed1993

Chondroitin sulfate proteoglycans are associated with the lesions of Alzheimer's disease.

Chondroitin sulfate proteoglycans (CSPG) are extracellular matrix proteins inhibitory to neurite outgrowth in vitro and correlated with decreased neurite outgrowth after CNS injury. Previously, heparan sulfate proteoglycan and dermatan sulfate proteoglycan have been shown to be associated with senile plaques (SPs) and neurofibrillary tangles (NFTs) but CSPG was not. In an immunocytochemical study, three monoclonal antibodies to different sulfation states of the chondroitin glycosaminoglycan were used to localize CSPG in cases of Alzheimer's disease. Chondroitin 4-sulfate was found in both SPs and NFTs. An antibody to unsulfated chondroitin strongly immunostained intracellular NFTs and the dystrophic neurites of SPs. Chondroitin 6-sulfate was found in NFTs and the area around SPs. These results suggest that CSPG, in addition or as an alternative to beta-amyloid protein, could be responsible for the regression of neurites around senile plaques in Alzheimer's disease.

Aged↗
PubMed1993

beta-Amyloid of Alzheimer's disease induces reactive gliosis that inhibits axonal outgrowth.

Pathological lesions in the brains of patients with Alzheimer's disease (AD) are characterized by dense deposits of the protein beta-amyloid. The link between the deposition of beta-amyloid in senile plaques and AD-associated pathology is, at present, controversial since there have been conflicting reports on whether the 39-43 amino acid beta-amyloid sequence is toxic or trophic to neurons. In this report, we show that beta-amyloid peptide when presented as an insoluble substrate which mimics its conformation in vivo can induce cortical glial cells in vitro and in vivo to locally deposit chondroitin sulfate containing proteoglycan. In vitro the proteoglycan-containing matrix deposited by glia on beta-amyloid blocks the usual ability of the peptide to allow cortical neurons to adhere and grow. Chondroitin sulfate-containing proteoglycan was also found in senile plaques of human AD tissue. We suggest that an additional effect of beta-amyloid in the brain, which compounds the direct effects of beta-amyloid on neurons, is mediated by the stimulation of astroglia to become reactive. Once in the reactive state, glial cells deposit large amounts of growth-inhibitory molecules within the neuropil which could impair neuronal process survival and regeneration leading to neurite retraction and/or dystrophy around senile plaques in AD.

Alzheimer Disease↗
PubMed1993

Immunochemical identification of ubiquitin and heat-shock proteins in corpora amylacea from normal aged and Alzheimer's disease brains.

Corpora amylacea (CA) accumulation in the central nervous system (CNS) is associated with both normal aging and neurodegenerative conditions such as Alzheimer's disease (AD). CA is reported to be primarily composed of glucose polymers, but approximately 4% of the total weight of CA is consistently composed of protein. CA protein resolved on sodium dodecylsulfate-polyacrylamide gel electrophoresis showed a broad range of polypeptides ranging from 24 to 133 kDa, with four abundant bands. Immunoblots of the profile of polypeptides solubilized from purified CA, showed positive ubiquitin (Ub) immunoreactivity for all the bands. Antisera to heat-shock proteins (hsp) 28 and 70 reacted selectively with bands of 30 and 67 kDa. These results show that Ub is associated with the primary protein components of CA and that the polypeptides are likely to be Ub conjugates. Immunostaining experiments were performed to specifically characterize the protein components of CA in brain tissue sections as well as those of CA purified from both AD and normal aged brains. In all cases CA showed positive reactions with antibodies to Ub, with antibodies raised against either paired helical filaments or hsp 28 or 70, the most prominent staining being with antibodies to Ub, hsp 28 or hsp 70. The presence of Ub and hsp 28 and 70, which are actively induced after stress, suggests that accumulation of altered proteins, possibly attributed to an increased frequency of unusual post-translational modifications or to a sustained physiological stress (related to both normal aging and neurodegenerative process), may be involved in the pathogenesis of CA.

Aged↗
PubMed1993

Neuritic plaques in Alzheimer disease originate from neurofibrillary tangles.

Amyloid beta-protein is a major focus in efforts to understand the etiology of Alzheimer disease yet there is little known about the mechanism of its deposition in plaques. I propose deposition of amyloid in neuritic plaques depends on the remains of neurofibrillary tangles after neuronal death. The interaction of these two lesions means neuritic plaques are not only dependent on neurofibrillary tangles and neuronal death but also dependent on their concurrence.

Alzheimer Disease↗
PubMed1993

Accumulation of the beta amyloid precursor protein at sites of ischemic injury in rat brain.

We used various antibodies to the beta amyloid precursor protein (APP) of Alzheimer's disease to study changes in the cellular distribution of APP in experimental ischemic brain injury. In contrast to sham operated controls, rats with repeated reversible occlusions of one middle cerebral artery showed striking APP reactivity in astrocytic processes in perifocal regions and white matter tracts. Dystrophic axons and neurons with accumulated APP were also evident in the ipsilateral neocortex and hippocampus. Such changes were also apparent in rats subjected to partial forebrain ischemia by bilateral occlusion of the carotid arteries. Our studies suggest that focal ischemic insults or chronic hypoperfusion leads to increased accumulation of APP in surviving brain cells that may pertain to enhanced beta amyloid deposition in Alzheimer's disease.

Amyloid beta-Protein Precursor↗
PubMed1993

The coelomic cavity: an important site of materno-fetal nutrient exchange in the first trimester of pregnancy.

OBJECTIVE: To measure levels of folate and vitamin B12 in matched samples of amniotic fluid and extra-embryonic coelomic fluid from 9 to 12 weeks' gestation. DESIGN: Prospective observational study. SETTING: Homerton Hospital, London. SUBJECTS: Twenty-two women with ultrasonographically normal pregnancies before surgical termination. METHODS: Transvaginal ultrasound-guided needle aspiration of amniotic fluid and extra-embryonic coelomic fluid was performed. Pure samples of amniotic fluid and extra-embryonic coelomic fluid were obtained from each pregnancy, and folate and vitamin B12 were measured using microbiological assays. RESULTS: Levels of folate and vitamin B12 were higher in extra-embryonic coelomic fluid than in amniotic fluid and maternal serum. Amniotic fluid folate levels were lower than in maternal serum whereas vitamin B12 levels in amniotic fluid were higher than in maternal serum. All differences in concentration were significant (P < 0.0005; paired t-test). Positive correlations were found between the concentrations of folate and vitamin B12 in each fluid. There was a linear correlation between gestational age and amniotic fluid folate levels (r = 0.648; P = 0.001). CONCLUSIONS: High concentrations of folate and vitamin B12 in coelomic fluid suggest that the coelomic cavity plays an important role in the materno-fetal exchange of these nutrients.

Amniotic Fluid↗
PubMed1993

Pharmacokinetics of rufloxacin in patients with impaired renal function.

The pharmacokinetics of rufloxacin were investigated in normal subjects and in patients with various degrees of renal failure after the administration of a single oral 400-mg dose. Twenty-four subjects were classified by glomerular filtration rate (GFR) normalized for body surface area. Group 1 subjects had GFRs of > 80 ml/min, group 2 subjects had GFRs from 30 to 80 ml/min, group 3 subjects had GFRs from 8 to 29 ml/min, and group 4 subjects had GFRs of < 8 ml/min. The patients in group 4 were on continuous peritoneal dialysis or underwent hemodialysis 48 h after dosing. Plasma and urinary rufloxacin concentrations were determined by high-performance liquid chromatography. A two-compartment model was used to calculate rufloxacin pharmacokinetic parameters. Apparent total body clearance of the drug was linearly related to GFR (r = 0.696; P < 0.01). The elimination half-life increased proportionally with the severity of renal impairment, with values of 30 +/- 3, 36 +/- 5, and 44 +/- 3 h in groups 1, 2, and 3, respectively. In patients with moderate renal failure, dosage adjustment of rufloxacin is not needed. The rufloxacin dose interval should be prolonged to 48 h as the GFR falls below 30 ml/min/1.73 m2.

Adult↗
PubMed1993

Immunocytochemical evidence that the beta-protein precursor is an integral component of neurofibrillary tangles of Alzheimer's disease.

Amyloid beta (A beta) immunoreactivity has been demonstrated in all extracellular neurofibrillary tangles (E-NFT) and most intraneuronal neurofibrillary tangles (I-NFT). We undertook this immunocytochemical study to understand the relationship between A beta immunoreactivity localized in NFT and beta-protein precursor (beta PP). We found epitopes of amino-, mid-, and carboxyl-terminal domains of beta PP in I-NFT and the majority of E-NFT. NFT retained beta PP after ionic detergent extraction, demonstrating that beta PP is an integral component of NFT. Finding beta PP in regions of A beta immunoreactivity raises the possibility that beta PP or its fragments associate with amyloid, and that the stability of A beta is responsible for its dominance in amyloid deposits.

Aged↗
PubMed1993

Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system.

Amyloid deposits are a characteristic feature of the senile plaques identified in the brains of aged primates, individuals with Down's syndrome, and cases of Alzheimer's disease. The beta-amyloid protein (A beta), the principal component of amyloid, is a 4 kDa peptide derived from larger amyloid precursor protein(s) (APP). Four mRNAs, generated by alternative splicing of pre-mRNA derived from a single gene, encode A beta-containing membrane glycoproteins termed APP-695, -714, -751, and -770; the latter two isoforms contain a domain homologous to Kunitz protease inhibitors (KPI). The present study uses in vitro and in vivo strategies to examine the expression of APP in neurons of the dorsal root ganglia and the nature of APP transported in sciatic nerves of rats. Using quantitative in situ hybridization and semiquantitative PCR analysis, we document that mRNAs encoding APP-695 are expressed preferentially over transcripts that encode KPI-containing isoforms in rat sensory ganglia. Furthermore, we provide compelling evidence that APP-695 is the predominant isoform synthesized in sensory neurons of the rat PNS and that full-length APP-695 and, to a lesser extent, APP-751/770 are rapidly transported anterogradely in axons.

Amino Acid Sequence↗