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Biomedical subjects

R N Kalaria

Publications and source records attributed to R N Kalaria.

At least 73 records · Page 4Linked to original sources
PubMed1995

Induction of heme oxygenase-1 mRNA and protein in neocortex and cerebral vessels in Alzheimer's disease.

Previous studies demonstrated the specific association of heme oxygenase (HO)-1 protein to the neurofibrillary pathology of Alzheimer's disease (AD). In this study, we used reverse transcription-polymerase chain reaction methods to show the increased expression of HO-1 but not HO-2 mRNA transcripts in cerebral cortex and cerebral vessels from subjects with AD compared with age-matched non-AD controls. Neither the HO-1 nor the HO-2 mRNA levels was altered in the cerebellum, a brain region usually spared from the pathological alterations of AD. There was no clear evidence that the expression of HO-1 in these tissues was related to postmortem interval, cause of death, or the age of the subjects studied. Using immunoblotting methods, we further showed that HO-1 protein content was increased in neocortical and vascular samples from AD subjects compared with controls. Our findings suggest the specific induction of HO-1 mRNA and protein in the cerebral cortex and cerebral vessels but not HO-2 mRNA or protein in association with the pathological lesions of the disease.

Aged↗
PubMed1995

Nicotinic receptors and neurodegenerative dementing diseases: basic research and clinical implications.

Nicotinic cholinergic agonists represent a relatively newly developing area for therapeutic intervention in Alzheimer disease (AD) and related neurodegenerative dementias. Loss of cholinergic receptors has been reported not only in AD but also in Parkinson's disease, Lewy body dementia, and progressive supranuclear palsy. Clinical studies suggest that compounds that act to stimulate nicotinic receptors may improve learning and memory in a variety of models of cognitive impairment in animals. Early clinical studies have suggested positive effects on cognition of nicotine in human beings with and without AD. Finally, nicotinic compounds might show the progression of AD, as suggested by preclinical models of cell death as well as epidemiological evidence of a protective effect of smoking in AD and Parkinson's disease.

Alzheimer Disease↗
PubMed1994

Nicotinic cholinergic receptors associated with mammalian cerebral vessels.

Current evidence suggests that the cerebral vasculature may be modulated by cholinergic nerves. We used ligand binding methods to examine the presence of nicotinic cholinergic receptors in brain vasculature. We found carbachol-displaceable [3H]acetylcholine (ACh) and [3H]nicotine (NIC) binding sites in preparations of intraparenchymal cerebral microvessels (CMV) and larger pial vessels from human and pig brains. Specific binding sites for [3H]ACh and [3H]NIC in cerebral microvessels were saturable and comparable in density to those in cerebral cortex. The Kds for the two ligands ranged 3-18 nM whereas the Bmaxs were 25-45 fmol/mg protein. In contrast, the binding of [3H]pirenzipine or [3H]quinuclidinyl benzilate, index for muscarinic receptors, was low (9-15% of cortex) in microvessels compared to the cerebral cortex. Our observations suggest the association of cholinergic nicotinic receptors with cerebral microvessels, which may be involved in the modulation of the cerebral circulation by cholinergic neurons.

Acetylcholine↗
PubMed1994

Heparan sulfate proteoglycan in diffuse plaques of hippocampus but not of cerebellum in Alzheimer's disease brain.

Previous studies have shown the basement membrane form of heparan sulfate proteoglycan (HSPG) known as perlecan, co-localized to beta-amyloid protein (A beta)-containing amyloid deposits in brains of patients with Alzheimer's disease (AD) and Down's syndrome. Although HSPG was localized to diffuse A beta plaques in hippocampus, amygdala, and neocortex, it is not known whether they are present in diffuse A beta plaques in cerebellum. In the present study, Alcian blue staining and immunocytochemical techniques were used to determine whether highly sulfated glycosaminoglycans (GAGs) and/or HSPG (perlecan) were also present in diffuse A beta plaques of cerebellum. Tissues from cases of AD were examined for the co-localization of highly sulfated GAGs, HSPGs, and A beta in diffuse plaques in cerebellum in comparison with hippocampus. Consecutive serial sections of AD brain tissue were stained or immunostained with 1) the modified Bielschowsky stain; 2) a polyclonal antibody directed against synthetic A beta (1-40); 3) Congo red; 4) Alcian blue (pH 5.7) with varying concentrations of magnesium chloride for identification of sulfated and highly sulfated GAGs; and 5) polyclonal and monoclonal antibodies recognizing either the core protein or a specific GAG epitope on perlecan. All cases (7 of 7) of AD contained diffuse A beta plaques in the cerebellum as identified by positive Bielschowsky staining and A beta immunoreactivity. None of these cases demonstrated positive Alcian blue staining (at 0.3 and 0.7 mol/L MgCl2), HSPG, or HS GAG immunoreactivity in the same diffuse cerebellar plaques on adjacent serial sections. However, Alcian blue staining, HSPG, and/or HS GAG immunoreactivity were observed in blood vessel walls, choroid plexus, and within Purkinje cells, suggesting that the techniques used were reliable and specific. In cerebellum, all plaques containing amyloid cores that were Congo red-positive were also positive for highly sulfated GAGs (by Alcian blue staining at 0.7 mol/L MgCl2) and HSPG (both core protein and GAG chain) immunoreactivity. Even though HSPG immunoreactivity was not present in cerebellar diffuse plaques, all cases (4 of 4) examined demonstrated HSPG (both core protein and GAG chain) immunoreactivity in diffuse A beta plaques in hippocampus. Therefore, by Alcian blue staining and immunocytochemical methods, highly sulfated GAGs and HSPGs are not present in A beta diffuse plaques in cerebellum. Since previous studies indicate that the cerebellum contains relatively few amyloid-containing plaques in comparison with diffuse plaques, these studies suggest that HSPG may be an essential component needed for amyloid formation and/or persistence in brain as observed in cortical areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1993

Amyloid P component and other acute-phase proteins associated with cerebellar A beta-deposits in Alzheimer's disease.

It is established that amyloid P (AP) component and complement proteins are associated with amyloid beta (A beta)-protein deposits in the cerebral cortex of Alzheimer's disease (AD) subjects. Here, we used immunocytochemical methods to examine the association of these acute-phase proteins with the characteristic diffuse plaques of cerebellum in AD. We observed AP and complement C3d, C1q, C5 and C4bp immunoreactivities in most A beta-protein-reactive plaques of the cerebellum. Further, a1-antichymotrypsin immunoreactivity was apparent in at least 60% of all the cerebellar diffuse plaques examined. Cerebellar tissue bearing the A beta-protein deposits also often exhibited marked angiopathy in the pial vessels. We suggest that diffuse plaques of the cerebellum also acquire components of the chronic inflammatory response evident in neocortical plaques.

Acute-Phase Proteins↗
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

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

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

Synaptic neurochemistry of human striatum during development: changes in sudden infant death syndrome.

There is evidence of abnormalities in the brain-stem monoamine-containing neurons in infants with sudden infant death syndrome (SIDS). By taking advantage of the rich innervation of the human basal ganglia by monoaminergic afferents from cell bodies in the brainstem, we studied the synaptic chemistry of catecholamine and associated neurons of the putamen obtained postmortem from 14 SIDS infants, eight age-matched control infants, and older control subjects of various ages. We found significantly lower concentrations of dopamine and higher homovanillic acid/DA ratios in samples from SIDS infants compared with age-matched control infants. Noradrenaline and 5-hydroxytryptamine were lower in SIDS compared with control subjects, but the difference did not reach statistical significance. There was no clear evidence that dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid were altered. Immunoblot analysis of striatal tissue showed that samples from infants with SIDS, which exhibited lower DA, also had lower tyrosine hydroxylase protein. Other transmitter-specific neuronal markers were also assessed, including enzymes associated with cholinergic and GABA-containing neurons. We found significantly decreased choline acetyltransferase activities. However, GABA, glutamate, or somatostatin concentrations or monoamine oxidase activities were unchanged in SIDS. We also noted age-dependent changes in brain weights and some synaptic markers by comparing the age-matched infants with older control subjects. Analysis of variance revealed that homovanillic acid, dihydroxyphenylacetic acid, and monoamine oxidase B activities were increased with age. DA and choline acetyltransferase were also found to be positively correlated in putamen. Our findings suggest developmental changes in some transmitter-specific neurons in SIDS that may result from apneic episodes or chronic hypoxia induced before death.

Acetylcholinesterase↗
PubMed1993

The immunopathology of Alzheimer's disease and some related disorders.

Current evidence clearly indicates that elements of the immune system are involved in the pathogenesis of the principal lesions characterizing Alzheimer's disease (AD). Findings are in accord with features associated with both the innate and adaptive immune mechanisms involved in a predominantly local inflammatory response within the parenchyma. Many of the features are unique to AD, presumably related to the unusual properties of beta amyloid protein. Remarkably, the brain holds the capacity to produce almost all the immune system mediators which largely seem to be generated by glia comprising both astrocytes and microglia. While a variety of humoral mediators including classical acute phase proteins (and serpins) are increased and released, the complement seems most intrinsically involved. The cellular response is elaborated by microglia which seem the main immunocompetent cells partaking in the response. These appear to function as pluripotent macrophages expressing both classes of MHC antigens. Further characterization of this interesting response to cerebral amyloidosis will be challenging.

Alzheimer Disease↗
PubMed1993

Long-term effects on pancreatic function of feeding a HC formula to rats during the preweaning period.

We have investigated pancreatic changes associated with hyperinsulinemia and an insulin secretory response to an oral glucose load in a new rat model for obesity. Male Sprague-Dawley pups were reared on a high-carbohydrate (HC) or high-fat (HF) formula by gastrostomy during the suckling period and were weaned onto a stock diet. These animals remained either nutritionally unchallenged or challenged with a high-sucrose diet during the postweaning period. The HC formula-fed animals showed increased insulin concentrations in the plasma and pancreas and also showed impaired insulin secretory response compared with mother-fed control or HF animals in adult life. Immunocytochemical and morphometric studies revealed that hyperinsulinemia in the HC animals during the preweaning period and also in adult life was associated with hypertrophy of beta-cells in the pancreas. The results show that consumption of a HC formula during the suckling period influences pancreatic islet morphology resulting in hyperinsulinemia which eventually leads to the development of obesity later in adult life.

Animals↗
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

Serine protease inhibitor antithrombin III and its messenger RNA in the pathogenesis of Alzheimer's disease.

The classical plasma protein antithrombin III (ATIII), an inhibitor of the blood coagulation cascade, is a member of the serpins that are gaining import in the nervous system. In this study, we examined the presence of ATIII in the pathological lesions of Alzheimer's disease (AD). Antibodies to ATIII consistently detected approximately 58-kd protein(s) on immunoblots of cerebral cortex and brain microvessels. Immunocytochemical studies showed ATIII reactivity within amyloid deposits, neurites associated with plaques, and neurofibrillary tangles in neocortex and hippocampus of virtually all the AD cases examined. In some cases, astrocytes were also stained, suggesting ATIII in these cells. ATIII immunoreactivity in neurofibrillary tangles was further defined by electron microscopy, which showed it to be associated with paired helical filaments. Using the polymerase chain reaction technique to amplify ATIII complementary DNA, we found low levels of messenger RNA expression, relative to liver, in control human brain samples, and these were increased in AD samples, particularly in the white matter. Our results suggest the increased presence of ATIII commensurate with astrogliosis and association with the neurofibrillary pathology of AD. We conclude that in concert with other amyloid-associated serine protease inhibitors, ATIII may play a role in the pathogenesis of cerebral amyloidosis.

Aged↗
PubMed1992

Complement inhibitor C4-binding protein in amyloid deposits containing serum amyloid P in Alzheimer's disease.

Complement C4-binding protein (C4BP) is a plasma protein that complexes with serum amyloid P and is involved in inhibition of the complement cascade. We used immunochemical methods to demonstrate C4BP in brains of subjects with Alzheimer's disease and normal controls. C4BP antibodies stained cerebral amyloid deposits that were indistinguishable from those recognized by antibodies to serum amyloid P or by thioflavin S. Immunoblots of solubilized proteins from cerebral cortex, cerebral microvessels and cerebrospinal fluid showed specific antibody reactivity to 70-90 kDa bands. Our results suggest the involvement of complement regulatory proteins in the pathogenesis of Alzheimer's disease.

Aged↗
PubMed1992

Transferrin receptors of rat and human brain and cerebral microvessels and their status in Alzheimer's disease.

We studied the regional distribution of specific [125I]transferrin binding to transferrin receptors in the brains and cerebral microvessels of humans and rats. We also assessed transferrin receptors in subjects with Alzheimer's disease. Human diferric [125I]transferrin bound to regional brain and cerebral microvessels with high affinity (dissociation constants of 1-10 nM), and the maximal binding densities ranged from 30 to 90 pmol/mg protein in the brain and were several-fold higher in cerebral microvessels. In Alzheimer's disease, transferrin receptor densities were significantly reduced in the hippocampus and the temporal and occipital cortex but were unchanged in the frontal and parietal cortex and the cerebellum. Although [125I]transferrin binding was higher in cerebral microvessels from subjects with Alzheimer's disease than in those of age-matched controls, this difference did not attain statistical significance. These results suggest that transferrin receptor density was decreased in some cortical areas including the hippocampus in Alzheimer's disease but relatively unchanged in cerebral microvessels.

Alzheimer Disease↗
PubMed1992

Identification of a stable fragment of the Alzheimer amyloid precursor containing the beta-protein in brain microvessels.

Altered proteolysis of the beta-amyloid precursor protein (beta APP) resulting in release of the approximately 40-residue amyloid beta-protein (A beta P) may be a seminal pathogenetic event in Alzheimer disease. Using region-specific beta APP antibodies, we searched for stable proteolytic intermediates containing the intact A beta P region in brain tissue. A 22-kDa beta APP fragment was selectively detected in microvessels purified from cerebral cortex and other brain regions. On immunoblots, the 22-kDa band is labeled by five distinct antisera to beta APP carboxyl-terminal peptides and by affinity-purified antibodies to the recombinant proteins beta APP444-592 and beta APP592-695, which flank the A beta P region. The protein is virtually undetectable in whole-brain homogenates or microvessel-free fractions of brain. The protein is extractable from microvessels in Triton X-100 and other detergents, indicating its membrane association. In comparison with cortical microvessels, microvessels purified from white matter, cerebellum, and nonneural tissues contain lower amounts of the 22-kDa protein. The protein is found in microvessels of both normal and Alzheimer disease brains and occurs in low amounts in microvessels from fresh bovine brain. The size and specific immunoreactivity of the 22-kDa protein indicate that it is a stable fragment of beta APP containing the intact A beta P. The occurrence of this potentially amyloidogenic intermediate in microvessels is consistent with a vascular or hematogenous origin for some A beta P deposits in Alzheimer disease.

Age Factors↗