Biomedical subjects

R N Kalaria

Publications and source records attributed to R N Kalaria.

At least 91 records · Page 5Linked to original sources

PubMed1992

Carnitine acetyltransferase activity in the human brain and its microvessels is decreased in Alzheimer's disease.

L-Carnitine and acetyl-L-carnitine facilitate mitochondrial beta-oxidation of fatty acids. In the brain, they may also have a role in acetylcholine synthesis. Carnitine acetyltransferase catalyzes the interchange between L-carnitine and acetyl-L-carnitine. Recently, acetyl-L-carnitine was reported to have a beneficial effect in patients with Alzheimer's disease. We therefore assessed carnitine acetyl-transferase activity in selected brain regions and in isolated cerebral microvessels obtained at autopsy from patients with Alzheimer's disease and from age-matched control subjects. We found a 25 to 40% decrease in carnitine acetyltransferase activity in patients with Alzheimer's disease, which attained statistical significance in most brain regions and in cerebral microvessels. These findings document another neurochemical abnormality in patients with Alzheimer's disease and provide a rationale for the use of acetyl-L-carnitine in the treatment of patients with Alzheimer's disease.

Aged↗

PubMed1992

Disease-specific patterns of locus coeruleus cell loss.

Computer visualization techniques were used to map and to quantitatively reconstruct the entire locus coeruleus, including the nucleus subcoeruleus, to compare the topographic patterns of cell loss in postmortem brains from patients with Parkinson's disease, Alzheimer's disease, and Down syndrome. There was comparable cell loss in all three diseases (approximately 60%) compared with aged normal subjects, and there was a significant loss of nucleus subcoeruleus cells specifically in patients with Parkinson's disease (63%). There was a significant positive correlation between the magnitude of locus coeruleus cell loss and the duration of Alzheimer's disease, but no such correlation was found for Parkinson's disease. In patients with Parkinson's disease, there was comparable cell loss throughout the rostral-caudal extent of the nucleus; however, in patients with Alzheimer's disease and Down syndrome, the greatest cell loss always occurred within the rostral portion of the nucleus, with a relative sparing of caudal cells. These data are consistent with the hypothesis that cell loss in Parkinson's disease is the result of a pathological process that attacks the catecholaminergic cells of the locus coeruleus and the subcoeruleus in general; in Alzheimer's disease and Down syndrome, however, the pathological process only affects the rostral, cortical-projecting locus coeruleus cells and spares the caudal, noncortical-projecting cells.

Aged↗

PubMed1992

Expression of leukocyte antigen CD34 by brain capillaries in Alzheimer's disease and neurologically normal subjects.

We studied the expression of a hemopoietic progenitor cell antigen, designated CD34, in brains from subjects with Alzheimer's disease (AD) and non-neurological controls. Immunoblots of brain microvessel proteins probed with monoclonal antibody QBEND/10 to the leukocyte antigen CD34 recognized a protein band with an apparent molecular mass of 90-100 kDa. Immunocytochemical staining of brain tissue sections showed CD34 to be expressed by all microvasculature including those of the circumventricular organs. In normal control brains such specific staining exhibited by QBEND/10 was indistinguishable from that obtained with collagen IV antibodies. In AD, however, increased vascular tendrils in form of endothelial abluminal processes and intraparenchymal abnormalities were evident in cortical and hippocampal regions, predominant in cases with severe pathology. Our results demonstrate that the leukocyte antigen CD34 is localized with the vascular endothelium throughout the human brain. These results also suggest that CD34 detects endothelial abnormalities in brains of AD subjects and support previous observations on the usefulness of CD34 to label abluminal microprocesses.

Aged↗

PubMed1992

Acetylcholinesterase and its association with heparan sulphate proteoglycans in cortical amyloid deposits of Alzheimer's disease.

Previous studies have used a sensitive histochemical technique to demonstrate acetylcholinesterase and butyrylcholinesterase within the pathological lesions of Alzheimer's disease. In this study, we used this technique to show that acetylcholinesterase localized in either frozen or fixed neocortical tissue sections is removed after treatment with various glycosaminoglycans, heparinases or proteases. Heparan sulphate, heparinase lyase type I and to a lesser degree, heparin and chondroitin sulphate were effective in solubilizing a large part of the cholinesterase activity. At physiological concentrations, the protease papain or trypsin readily removed activity but collagenase or pronase were relatively less effective. Peptide protease inhibitors and divalent metals did not exhibit any clear effect. The specificity of these observations was shown by inhibition of activity with various anticholinesterases including diisofluorophosphate. Our results suggest that acetylcholinesterase is anchored to and may be released from the heparan sulphate glycosaminoglycans shown to be contained in the lesions. We further suggest that the localization of cholinesterases is closely associated with the accumulation of the glycosaminoglycans in amyloid plaques and neurofibrillary tangles.

Acetylcholinesterase↗

PubMed1992

Alpha 1-antitrypsin and alpha 1-antichymotrypsin are in the lesions of Alzheimer's disease.

We performed immunocytochemistry to localize alpha 1-antichymotrypsin and alpha 1-antitrypsin in tissue sections of Alzheimer disease patients. Our results show that both serine protease inhibitors are localized in neurofibrillary tangles and senile plaques. Using various monoclonal and polyclonal antibodies, immunolabeling was evident in formalin, methacarn or acetone-fixed sections. Brief pretreatments of sections with either formic acid or guanidine-HCl were also necessary to reveal clear immunostaining of the lesions with two of the antibodies. We suggest that both alpha 1-antitrypsin and alpha 1-antichymotrypsin may be functionally involved in the pathogenesis of the lesions of Alzheimer's disease. Like alpha 1-antichymotrypsin, the major cell producing alpha 1-antitrypsin is likely to be astrocytes since the protein was localized there and astrocytes are involved in both lesions.

Aged↗

PubMed1992

The blood-brain barrier and cerebral microcirculation in Alzheimer disease.

Current evidence does not preclude the possibility that breach of the blood-brain barrier (BBB) is causally involved in the pathogenesis of Alzheimer disease (AD). There is abundant evidence, however, indicating morphological and biochemical abnormalities in the cerebral microvasculature that implicate breakdown of the BBB in AD. These abnormalities include profound irregularities in the course of vessels and the vascular basement membrane, changes in specific proteins and receptors associated with the cerebral endothelium, and increases in perivascular infiltrates. While noninvasive imaging and permeability studies provide no clear functional evidence to support the prevailing morphological evidence, focal and transient loss of integrity of the BBB in AD is probable. Thus, neuronal populations in circumscribed areas could become vulnerable. Cerebral amyloid angiopathy (CAA) is one of the pathological features highly associated with AD that may exacerbate the degenerative process. CAA may develop as a consequence of vascular changes at predisposed sites and precede at least some of the parenchymal amyloid deposits. It is not unlikely that many of these vascular changes contribute to the development of chronic hypoperfusion (or cerebrovascular insufficiency) that may lead to the progressive decline of cerebral functions in concert with aging.

Alzheimer Disease↗

PubMed1991

Widespread serum amyloid P immunoreactivity in cortical amyloid deposits and the neurofibrillary pathology of Alzheimer's disease and other degenerative disorders.

Amyloid P (AP) component is present in all types of systemic amyloid deposits. Recently, it has been shown to be also present in cerebral amyloid lesions of Alzheimer's disease (AD). In this study, we used immunocytochemical methods to extend these findings at the electron microscope level and characterize the spectrum of AP immunoreactivity in neurofibrillary pathology (NFP) of AD and other neurodegenerative disorders including Down's syndrome (DS), Creutzfeldt-Jakob, Parkinson's, Pick's and diffuse Lewy body diseases and progressive supranuclear palsy. In AD and DS, AP immunoreaction product was evident in all the classical amyloid lesions and NFP in a large sample of all cortical areas examined. The distribution and relative intensity of immunostaining was similar to that of thioflavin S staining in serial sections. In many cases, however, plaques and vessels stained by anti-AP serum were not apparent with thioflavin S. Serial sections immunostained with antiserum to amyloid A, C-reactive protein or to other proteins involved in systemic amyloidoses and the acute phase response showed no evidence of staining in any of the cerebral lesions. Electron microscopy confirmed that AP immunoreactivity was associated with the abnormal filaments characteristic of NFP as well as amyloid fibrils found in plaques and vessels showing congophilic amyloid angiopathy. Plaques of Creutzfeldt-Jakob disease, Pick bodies of Pick's disease, tangles and Lewy bodies in Parkinson's disease and a subpopulation of Lewy bodies in the diffuse Lewy body disease coexistent with AD were also stained. With the exception of vessels in two of the five cases, AP was not detected in age-matched controls. Our observations indicate AP to be a consistent feature of cerebral NFP and amyloid deposits.

Adult↗

PubMed1991

Blood-brain barrier abnormalities in Alzheimer's disease.

We studied the cerebral microcirculation and the blood-brain barrier in Alzheimer's disease by assessing the glucose transporter, several functionally important enzymes, and adrenergic receptors in isolated brain microvessels that were obtained at autopsy from subjects with Alzheimer's disease and from age-matched controls. We found a marked decrease of about 50% in the density of the glucose transporter, but increased densities of beta 2- and alpha 2-adrenergic receptors in cerebral microvessels obtained from subjects with Alzheimer's disease. The biologic implications of these findings are discussed.

Alzheimer Disease↗

PubMed1991

Serum amyloid P in Alzheimer's disease. Implications for dysfunction of the blood-brain barrier.

We describe widespread serum amyloid P (AP) immunoreactivity in cerebral lesions including neurofibrillary tangles, senile plaques, and vessels in Alzheimer's disease (AD). To elucidate the mechanisms of its origin in cerebrospinal fluid and localization in brain, we searched for AP mRNA by the polymerase chain reaction. Our findings show that with the exception of liver, AP mRNA was not detectable in any of the brain regions tested or choroid plexus. These observations support extravasation or transport of this serum protein across the blood-brain barrier or the blood-cerebrospinal fluid barrier in the brain of subjects with AD.

Alzheimer Disease↗

PubMed1991

Association of heparan sulfate proteoglycan with the neurofibrillary tangles of Alzheimer's disease.

The major intracytoplasmic lesion of Alzheimer's disease is the neurofibrillary tangle (NFT), which is primarily composed of paired helical filaments (PHFs). The mechanism responsible for the formation of PHFs, as well as their insolubility and apparent heterogeneity, is unknown. We found that basic fibroblast growth factor (bFGF) binds to heparinase-sensitive sites in NFTs. bFGF binding is due to a heparan sulfate proteoglycan (HSPG) immunocytochemically identified in NFTs. In the presence of polycations (e.g., Ca2+), HSPG will bind to free carboxyl groups in NFT proteins. HSPG binding may play a role in transforming normal soluble proteins into insoluble PHFs.

Aged↗

PubMed1990

Hippocampal adenosine A1 receptors are decreased in Alzheimer's disease.

Previous studies showed that adenosine receptors of the temporal and frontal cortices were not affected in Alzheimer's disease (AD). Here, we assessed the specific binding of [3H]cyclohexyladenosine to adenosine1 (A1) receptors in hippocampus from AD subjects and age-matched controls. By both particulate membrane and in vitro autoradiographic receptor binding methods we demonstrate that A1 receptors are significantly reduced by 40-60% in AD subjects. Scatchard analysis showed that maximum binding capacity (Bmax) was affected and there was no evidence for a change in the affinity of the receptor for the ligand (Kd). Receptor autoradiography revealed that although several regions including CA1, CA3 and deep layer of the subiculum were affected, the loss in A1 receptors was most prominent in the molecular layer of the dentate gyrus. In view of previous evidence indicating that these receptors are associated with the perforant pathway and dendritic fields of the CA1 and CA3 regions, our findings suggest loss of the presynaptic A1 receptors on axon terminals of extrinsic pathways including the perforant path and intrinsic pyramidal neurons which release glutamate.

Adenosine↗

PubMed1990

Serum amyloid P immunoreactivity in hippocampal tangles, plaques and vessels: implications for leakage across the blood-brain barrier in Alzheimer's disease.

Serum amyloid P (SAP) has been shown to be consistently present in all types of amyloid deposits except cerebral lesions of neurofibrillary tangles and senile plaques. We used immunohistochemical methods to demonstrate SAP reactivity in both tangles and plaques, as well as vessels, in lightly fixed frozen tissue sections of hippocampus and parahippocampal gyrus from subjects with Alzheimer's disease (AD) and normal controls. As confirmed by thioflavin S staining, heavy deposition of immunoperoxidase reaction product was evident in Sommer's sector (CA1), the subiculum and entorhinal cortex with both the antisera to SAP used. Serial sections immunostained with antiserum to amyloid A or preimmune rabbit serum showed no evidence for staining in plaques or tangles. These observations provide evidence for extravasation of the protein across the blood-brain barrier (BBB) in disease although expression of it by cellular elements within or entering the brain through the BBB cannot be ruled out. Our results also implicate the use of lightly fixed tissue for localization of some antigens by immunohistochemistry in postmortem human brain.

Aged↗

PubMed1990

Glucose transporters are abundant in cells with "occluding" junctions at the blood-eye barriers.

We studied the distribution of the "erythroid/brain" glucose transporter protein in the human and rat eye by immunocytochemistry with monoclonal and polyclonal antibodies to the C terminus of the human erythrocyte glucose transporter. We found intense immunocytochemical staining in the endothelium of microvessels of the retina, optic nerve, and iris but not in microvessels of the choroid, ciliary body, sclera, and other retro-orbital tissues. In addition, we found marked immunocytochemical staining of retinal pigment epithelium, ciliary body epithelium, and posterior epithelium of the iris. The common feature of all those endothelial and epithelial cells that stained intensely for the glucose transporter is the presence of "occluding" intercellular junctions, which constitute the anatomical bases of the blood-eye barriers. We propose that a high density of the glucose transporter is a biochemical concomitant of epithelial and endothelial cells with barrier characteristics, at least in tissues that have a high metabolic requirement for glucose.

Animals↗

PubMed1990

The relationship of amyloid plaques to cerebral capillaries in Alzheimer's disease.

The authors examined the hypothesis that senile plaques of Alzheimer's disease (AD) are formed by abnormal leakage of amyloidogenic precursors from brain capillaries by quantitative analysis of the spatial relationship between capillaries and amyloid plaques. Vibratome sections (40 mu) of the hippocampus, including the entorhinal cortex, obtained at autopsy from AD subjects, were immunostained with a monoclonal antibody to beta-protein and counterstained with rabbit serum to either the glucose transporter protein, a cerebral endothelial marker, or collagen type IV, a basal lamina marker. The authors found that while 60% to 77% of amyloid plaques were associated with capillaries, only 8% to 13% were penetrated by a capillary, the remainder being adjacent. To test whether 1) the area occupied by amyloid plaques or 2) the border zone (10-mu rim) surrounding amyloid plaques has a statistically higher density of capillaries than 3) the remaining gray matter, similarly double-stained 6-mu sections from five AD subjects were photographed and the capillary densities in the three areas calculated. Capillary density was significantly lower in 1) than in 3) and higher in 2) than in 3), while the combined area of 1) and 2) showed the same capillary density as 3). Similar results were obtained by using either the glucose transporter or the collagen type IV antibodies. Because capillary density is low within, and high in regions that immediately surround amyloid plaques, our findings suggest that amyloid plaques exclude capillaries or lead to their degeneration, or both. The latter possibility was investigated by triple-staining tissue sections with antibodies to beta-protein, glucose transporter, and collagen type IV. The proportion of glucose transporter-negative capillaries was not significantly different in areas inside or outside of the plaques. Thus, the authors found no evidence of basal lamina remnants consistent with capillary degeneration preferential to amyloid plaques. Although a small number of capillaries showed amyloid deposition just beneath the basement membrane, the authors conclude that capillaries play only a limited direct role, if any, in amyloid plaque formation, and that the apparent association of amyloid plaques and capillaries is no more than a chance contact.

Alzheimer Disease↗

PubMed1990

Immunocytochemical localization of the erythroid glucose transporter: abundance in tissues with barrier functions.

We investigated the cellular localization and tissue distribution of the glucose transporter protein in the nervous system of the monkey and rat, and in other tissues of the rat, by immunocytochemical methods with monoclonal and polyclonal antibodies to the glucose transporter of human erythrocytes. We found intense immunostaining, indicating a high density of the glucose transporter, in all intraparenchymal blood vessels of the brain and spinal cord, in pial vessels, and in endoneurial capillaries of peripheral nerves, nerve roots, and dorsal root ganglia. Larger blood vessels at the base of the brain and in major fissures did not stain. The only intraparenchymal brain microvessels that did not immunostain were in circumventricular organs. There was no specific immunostaining of neurons or glia, except for tanycytes in the floor of the third ventricle, which immunostained intensely. Vessels of the choroid plexus did not stain, but the choroid epithelium, especially its basal membranes, stained. The only non-neural organ where immunostaining was evident in its microvessels was the testis. In addition to the endothelium of neural and testicular tissues, there was immunostaining in certain epithelial tissues, such as the perineurium of peripheral nerves and nerve roots, the epithelium of the ascending loop of Henle in the kidney, and the epidermis of the skin. Based on these findings, we hypothesize that a high density of the erythroid-type glucose transporter is inherent to many endothelial and epithelial cells that are joined by occluding junctions. However, other epithelial tissues with known occluding intercellular junctions that lack the erythroid-type of glucose transporter may have other types of glucose transporter proteins.

Animals↗

PubMed1989

Increased alpha 2- and beta 2-adrenergic receptors in cerebral microvessels in Alzheimer disease.

Adrenergic receptors exist in brain microvessels which are innervated by noradrenergic locus ceruleus neurons. Biochemical and pathological studies indicate locus ceruleus degeneration in Alzheimer disease (AD), which can cause adrenergic receptor alterations in brain microvessels. To assess this, we studied adrenergic receptors in human brain microvessels from AD subjects and age-matched controls by ligand binding methods. Total beta receptors of cerebral microvessels and beta 2 receptors, the type which predominates in microvessels, were significantly increased in AD. Compared to the cerebral cortex, there was a paucity of alpha 1-adrenergic receptors in cerebral microvessels, and they did not change in AD. Binding to alpha 2 receptors in cerebral microvessels was approximately 50% of that in the cortex, and these receptors increased by approximately 60% in cerebral microvessels of AD subjects. These findings suggest adrenergic receptor 'upregulation' in response to noradrenergic deafferentation in AD, which may have functional consequences at the blood-brain barrier.

Aged↗

PubMed1989

Characterization of [125I]HEAT binding to alpha 1-receptors in human brain: assessment in aging and Alzheimer's disease.

The binding of [125I]2-(beta-4-hydroxyphenylethylamino-ethyltetralone ([ 125I]HEAT), an alpha 1-adrenergic receptor antagonist, to human brain membranes was characterized and the binding assessed in tissue from subjects with Alzheimer's disease (AD) and aging controls. Under Na+-K+ phosphate buffer conditions, [125I]HEAT bound to a single class of binding sites in prefrontal cortex (Brodmann area 10) with a Kd of about 120 pM. High binding capacities of [125I]HEAT were evident in the hippocampus and neocortex but were low in subcortical areas and cerebral microvessels comparable to the regional distribution of [3H]prazosin binding reported previously. Displacement of [125I]HEAT by various adrenergic drugs was consistent with its binding to alpha 1-adrenergic receptors. The specific binding was not affected by postmortem delay between death and freezing of tissue at autopsy. There was no correlation of [125I]HEAT binding with age of subjects. In AD subjects, the binding was significantly decreased in prefrontal cortex by about 25% but not changed in hippocampus, putamen or cerebellum compared to age-matched controls. The reduced binding of [125I]HEAT in prefrontal cortex may reflect a region-specific change in alpha 1-adrenergic receptors associated with neuronal loss in AD.

Aged↗

PubMed1989

Brain microvessels are innervated by locus ceruleus noradrenergic neurons.

Noradrenergic fibers from the locus ceruleus were identified in close proximity to brain microvessels, and adrenoceptors exist in isolated brain capillaries. Yet, proof of innervation of brain microvessels by locus ceruleus remains elusive. We now demonstrate increased density of beta-adrenoceptors by pindolol binding in microvessels isolated from the norepinephrine-depleted cerebrum two weeks after locus ceruleus lesion or reserpine treatment. This finding of 'denervation supersensitivity' in brain microvessels implies that their adrenoceptors respond to norepinephrine from the locus ceruleus, and strongly suggests that the locus ceruleus innervates brain microvessels. These results may have important implications because blood-brain barrier dysfunction may be a factor in the pathophysiology of Alzheimer dementia and Parkinson disease, which are associated with locus ceruleus degeneration.

Adrenergic Fibers↗