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Biomedical subjects

E H Koo

Publications and source records attributed to E H Koo.

At least 73 records · Page 4Linked to original sources
PubMed1991

Studies on the proteolytic degradation of the beta-protein precursor by proteases purified from Alzheimer's disease brain.

In Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of Dutch origin, and normal aging, amyloid accumulates in the brain parenchyma and blood vessels. The major protein in the deposits is the beta-protein, a 4-kD peptide possibly generated by an abnormal degradation of its precursor, the beta-protein precursor (beta PP). We found, as a second component of the brain amyloid, the serine protease inhibitor alpha 1-antichymotrypsin (ACT). Inasmuch as ACT is tightly associated with the beta-protein and is never found in other amyloidoses, we hypothesized a role for ACT in the degradation of the beta PP. We used synthetic peptides made according to the sequence flanking the N-terminus of the beta-protein to screen brain fractions for protease activity. After several purification steps, two protease fractions were found that can cleave the peptide between methionine and aspartic acid, aspartic acid being the N-terminus of the beta-protein. One protease is activated by calcium and inhibited by ACT, beta PP containing the Kunitz-type inhibitory domain, diisofluorophosphate, and 1,10-phenanthroline. This protease fraction is also able to degrade the beta PP in vitro. The second protease is a metal-dependent cysteine protease.

Alzheimer Disease↗
PubMed1991

Aged non-human primates: an animal model of age-associated neurodegenerative disease.

Aged non-human primates develop age-associated behavioral and brain abnormalities similar to those that occur in aged humans and, to a greater extent, in individuals with Alzheimer's disease. Declines in performance on cognitive and memory tasks begin at the monkey equivalent of late-middle life. As occurs in elderly humans, significant differences have been demonstrated in levels of performance between animals within older age groups. The brains of old monkeys show degenerative changes in neurons, abnormal axons and neurites (particularly in telencephalic areas), and deposits of amyloid in senile plaques and around blood vessels. Moreover, in some older animals, decrements occur in markers of specific neurotransmitter circuits, including the basal forebrain cholinergic system. It has been suggested that alterations in these cholinergic neurons contribute to the memory deficits that occur in older individuals. Because axotomy-induced retrograde degeneration of these neurons can be prevented by the administration of nerve growth factor, we have begun studies to determine whether administration of nerve growth factor improves performance of aged animals on memory tasks. This review describes the complementary nature of studies of non-human primates and human subjects, illustrating how these investigations can clarify factors that influence behavior and brain biology in age-associated diseases.

Aging↗
PubMed1990

Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing.

The beta-amyloid protein (beta/A4), derived from a larger amyloid precursor protein (APP), is the principal component of senile plaques in Alzheimer's disease. APP is an integral membrane glycoprotein and is secreted as a carboxyl-terminal truncated molecule. APP cleavage, which is a membrane-associated event, occurred at a site located within the beta/A4 region. This suggests that an intact amyloidogenic beta/A4 fragment is not generated during normal APP catabolism. Therefore, an early event in amyloid formation may involve altered APP processing that results in the release and subsequent deposition of intact beta/A4.

Aged↗
PubMed1990

Differential expression of amyloid precursor protein mRNAs in cases of Alzheimer's disease and in aged nonhuman primates.

Senile plaques are a characteristic feature in brains of individuals with Alzheimer's disease (AD) and aged monkeys. The principal component of amyloid in senile plaques is beta/A4, a peptide derived from a larger amyloid precursor protein (APP). To date, several alternatively spliced APP transcripts have been described. The relationship between levels of these APP mRNAs and amyloid deposition is unclear. In this study, we directly measured the relative levels of APP transcripts that lack the protease inhibitor domain (APP-695) and transcripts that encode the inhibitor sequences (APP-751/770). Our results indicate that the expression of APP mRNAs is not selectively altered in AD cortex. Moreover, the differential expression of APP transcripts is not correlated with the deposition of amyloid in cases of AD and aged monkeys. These findings suggest that other factors, not directly related to the relative expression of APP mRNAs, may contribute to amyloidogenesis in the brain.

Aging↗
PubMed1990

Neuronal responses to injury and aging: lessons from animal models.

Alzheimer's disease (AD), the most common type of adult-onset dementia, is characterized by a variety of brain abnormalities, including degeneration of certain populations of nerve cells, alterations in the neuronal cytoskeleton, and the abnormal deposition of amyloid within brain parenchyma. Pathogenetic processes that lead to these brain abnormalities are difficult to study in humans. Recently, investigators have begun to utilize animal models to examine some of the mechanisms that cause cellular/molecular alterations in transmitter systems, cytoskeletal elements, and APP. These investigations have helped to clarify issues related to the lesions that occur in aged humans and individuals with AD.

Aging↗
PubMed1990

Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport.

In the brains of aged humans and cases of Alzheimer disease, deposits of amyloid in senile plaques are located in proximity to nerve processes. The principal component of this extracellular amyloid is beta/A4, a peptide derived from a larger amyloid precursor protein (APP), which is actively expressed in brain and systemic organs. Mechanisms that result in the proteolysis of APP to form beta/A4, previously termed beta-amyloid protein, and the subsequent deposition of the peptide in brain are unknown. If beta/A4 in senile plaques is derived from neuronally synthesized APP and deposited at locations remote from sites of synthesis, then APP must be transported from neuronal cell bodies to distal nerve processes in proximity to deposits of amyloid. In this study, using several immunodetection methods, we demonstrate that APP is transported axonally in neurons of the rat peripheral nervous system. Moreover, our investigations show that APP is transported by means of the fast anterograde component. These findings are consistent with the hypothesis of a neuronal origin of beta/A4, in which amyloid is deposited in the brain parenchyma of aged individuals and cases of Alzheimer disease. In this setting, we suggest that APP is synthesized in neurons and delivered to dystrophic nerve endings, where subsequent alterations of local processing of APP result in deposits of brain amyloid.

Acetylcholinesterase↗
PubMed1990

Neuronal disorders: studies of animal models and human diseases.

The peripheral nervous system and the central nervous system (CNS) are comprised of assemblies of neurons that communicate via electrical and chemical signals. Different disease processes selectively affect specific populations of neurons and/or specific cell functions (i.e., "selective vulnerability" of neurons is a principal determinant of phenotypes of disease). New cellular and molecular biological approaches have begun to clarify some of the mechanisms of selective cell injury in human diseases and their animal models. Following a brief review of the normal biology of nerve cells, we use illustrations drawn from studies of experimental and human diseases to discuss the mechanisms of structural/chemical abnormalities that occur in a variety of neuronal disorders.

Animals↗
PubMed1988

Levels of neurotransmitter and cytoskeletal protein mRNAs during nerve regeneration in sympathetic ganglia.

The present study examines levels of neurotransmitter messenger RNA (mRNA) at various stages after crush of postganglionic nerves in the superior cervical ganglia. Using complementary DNA (cDNA) probes, we demonstrated a reduction in ganglionic mRNA levels for tyrosine hydroxylase (TH) after axotomy. Concomitantly, actin and tubulin mRNA levels in ganglia were increased. Thus, in neurons of sympathetic ganglia, axotomy appears to be associated with a selective reduction in levels of TH mRNA, and, in turn, alters levels of protein and enzyme activities.

Actins↗
PubMed1988

Aluminum neurotoxicity: altered expression of cytoskeletal genes.

To better understand perturbations of the neuronal cytoskeleton that occur in several mammalian disorders, we have focused on an animal model in which neurofibrillary pathology follows the administration of aluminum salts. In susceptible species, the injection of aluminum produces accumulations of neurofilaments (NFs) in cell bodies and proximal axons of certain populations of neurons. Mechanisms involved in the production of these abnormalities are unclear; in particular, the role of gene expression in the genesis of this type of neurofibrillary pathology has not been examined. In this study of aluminum-intoxicated rabbits, the expression of genes coding for several cytoskeletal proteins was studied in the spinal cord and dorsal root ganglia (DRG)--tissues with and without neurofibrillary pathology, respectively. In aluminum-treated rabbits, in situ hybridization using a cDNA probe demonstrated the presence of mRNA coding for the 68-kDa NF (NF-L) protein in spinal cord motor neurons with NF accumulations as well in unaffected neurons. On Northern blots, the expression of genes coding for the NF-L protein and tubulin was reduced by approximately 3.5-fold and 3-fold, respectively, in spinal cords of aluminum-intoxicated rabbits as compared to controls. On blots, levels of actin mRNA were not significantly different in spinal cords of aluminum-treated rabbits as compared to controls, but there was a trend for a slight reduction. In DRG of intoxicated animals, the expression of genes coding for these cytoskeletal proteins was not altered.

Aluminum↗
PubMed1988

Granulomatous angiitis of the central nervous system: protean manifestations and response to treatment.

Granulomatous angiitis is an uncommon necrotising vasculitis of unknown cause restricted to vessels of the central nervous system. Five tissue-proven cases emphasise the protean manifestations of this disease and the difficulties encountered in reaching a diagnosis. One patient presented with a temporoparietal mass, the second, a progressive dementia, the third suggested herpes simplex encephalitis, the fourth mimicked multi-infarct state; and the fifth presented with a cerebellar mass lesion. In four cases with CSF examination, protein was elevated (81-193 gm/l) and three patients had mononuclear pleocytosis (12-800 WBC/mm3). Cerebral arteriogram suggested vasculitis in only one of four cases. Diagnosis was made by brain biopsy in three cases and all three were treated successfully. The diagnosis in the two other cases was made at postmortem examination.

Adult↗
PubMed1987

Motoneuron loss in the abducens nucleus of wobbler mice.

The 'wobbler' mutant mouse can be recognized at about 4 weeks of age by its tremor and atrophy of forelimb muscles. In addition to degeneration of spinal motoneurons, especially in cervical spinal cord, selected bulbar motoneurons have also been reported to degenerate in the mutant. We examined a cranial motor nucleus and found a 31% loss of abducens motoneurons in 4-5-week-old wobbler mice as compared to age-matched control mice.

Abducens Nerve↗
PubMed1987

beta-Amyloid gene is not present in three copies in autopsy-validated Alzheimer's disease.

Recently, it has been suggested that Alzheimer's disease is associated with a duplication of the amyloid precursor protein gene localized to chromosome 21q21. In this study, a cloned DNA probe (B2.3), complementary to the sequence coding the beta-amyloid peptide, and DNA polymorphisms adjacent to this sequence were used to determine the number of copies of the beta-amyloid gene in DNA isolated from human blood and brain. Individuals with trisomy 21 (Down syndrome) who were heterozygous for the polymorphisms showed a gene-dosage effect, with one allele exhibiting twice the autoradiographic intensity as the other. Heterozygous individuals with Alzheimer's disease and controls showed equal intensities of the two allelic bands, suggesting that there are only two copies of the beta-amyloid gene in these individuals. In individuals with Alzheimer's disease and in controls who were homozygous for these polymorphisms, the number of copies of the beta-amyloid gene was determined by comparing the autoradiographic intensity of beta-amyloid alleles to that of DNA fragments detected by a reference probe. No difference was detected between these two groups.

Alzheimer Disease↗
PubMed1986

Therapy for granulomatous angiitis.

The clinical diagnosis of granulomatous angiitis can be extremely difficult because of the diversity of presentation. A clinical presentation of progressive multifocal encephalopathy is most common but signs suggesting isolated mass lesions or dementia may be seen. Laboratory studies are helpful, particularly when CSF examination reveals elevated protein or a mononuclear cell response. Cerebral angiogram may demonstrate vasculitis but tissue biopsy is extremely important in firmly establishing a diagnosis. Leptomeningeal biopsy should be performed before initiation of appropriate immunosuppressive therapy and before major irreversible loss of neurologic function occurs. Corticosteroid therapy is the initial treatment of choice, although recent anecdotal reports suggest additional benefits of immunosuppressive drugs such as cytoxan in refractory cases. Whether immunosuppressive drugs should be added routinely cannot be ascertained at present. However, in view of the likelihood of an extended period of treatment, and perhaps relapses when treatment is discontinued, the need to establish an unequivocal diagnosis is of utmost importance when treating with potentially hazardous drugs.

Adrenal Cortex Hormones↗
PubMed1981

The melanocytotoxicity of gamma-L-glutaminyl-4-hydroxybenzene: a study of the pigmented cells in the mouse eye.

The administration of gamma-L-glutaminyl-4-hydroxybenzene (GHB) to neonatal black mice resulted in selective necrosis of the melanocytes in the choroid but had no apparent effect on the retinal pigment epithelium and pigmented cells of the iris and ciliary body. No changes were noted in any of the ocular melanocytes when GHB was administered to adult black mice or neonatal albino mice. The administration of p-aminophenol, which may be a metabolite of GHB in mammalian cells, produced identical cytologic changes in the eyes of neonatal black mice. The findings indicate that in the presence of an active melanogenic environment, the metabolism of GHB generates products that are promptly cytolytic. In the immature retina of both black and albino mice, the administration of GHB also resulted in scattered necrosis in the inner layer of the developing neuroblastic cells in the form of cellular condensation. This effect, which is independent of the process of melanogenesis, could not be elicited beyond the fifth postnatal day and may represent a quantitative exaggeration of a normal cellular phenomenon.

Age Factors↗
PubMed1980

Melanocytotoxicity and the mechanism of activation of gamma-L-glutaminyl-4-hydroxybenzene.

gamma-L-Glutaminyl-4-hydroxybenzene is converted by the tyrosinase of the common mushroom, Agaricus bisporus, to the toxic, dormancy-inducing metabolite 2-hydroxy-4-imino-2,5-cyclohexadiene-1-one. Hydroxylation of gamma-L-glutaminyl-4-hydroxybenzene by mammalian tyrosinase was monitored by determining tritium water release from gamma-L-glutaminyl-[3,5-(3)H[4-hydroxybenzene and occurred at only 25% of the rate found with tyrosine. The dihydroxy product of the hydroxylation reaction, gamma-L-glutaminyl-3,4-dihydroxybenzene, was not oxidized by the mammalian enzyme. Therefore, oxidation of gamma-L-glutaminyl-4-hydroxybenzene to sulfhydryl-reactive quinones by mammalian tyrosinase is an unlikely explanation for the hair depigmentation and inhibition of melanocarcinoma growth observed following administration of this compound. Cleavage of gamma-L-glutaminyl-4-hydroxybenzene by gamma-glutamyl transpeptidase releasing p-aminophenol was demonstrated. p-Aminophenol was an active depigmenting and melanocytotoxic compound. N2-Methyl-gamma-L-glutaminyl-4-hydroxybenzene was synthesized, differing from gamma-L-glutaminyl-4-hydroxybenzene only by the presence of a methylated amide linkage. This chemical modification resulted in a compound resistant to cleavage by gamma-glutamyl transpeptidase and lacking in melanocytotoxic activity. gamma-Glutamyl transpeptidase cleavage is proposed as the route for transformation of gamma-L-glutaminyl-4-hydroxybenzene into an active inhibitor of melanocytes.

Aminophenols↗
PubMedDate not supplied

Cellular and molecular biology of Alzheimer's disease.

Alzheimer's disease results from the degeneration of neurons. Degenerating nerve cells express atypical proteins, and amyloid is deposited. We suggest that some of these events are strongly influenced by genetic factors and age. Animal models should be useful in investigating the pathogenic mechanisms that lead to the brain abnormalities seen in this disease.

Alzheimer Disease↗
PubMedDate not supplied

Developmental expression of alpha 1-antichymotrypsin in brain may be related to astrogliosis.

In the brains of individuals with Alzheimer's disease (AD) and aged monkeys, the serine protease inhibitor alpha 1-antichymotrypsin (ACT) is selectively associated with deposits of amyloid found in senile plaques and in the walls of blood vessels. The origin of ACT in the brains of these aged subjects is unclear. In this study, ribonucleic acid (RNA) blots of human brains show that ACT messenger RNA (mRNA) increases during development. Levels of mRNA were negligible in fetuses and young adults but were increased slightly in normal aged individuals and highest in individuals with AD. In situ hybridization detected ACT transcripts in astrocytes of the cortex, subependymal region, and superficial white matter. The expression of ACT mRNA was highest in subjects with AD, in an adult with Down's syndrome, in an individual with Pick's disease, and in cases of Huntington's disease. In the brains of adult monkeys, ACT expression was detected primarily in astrocytes of the subependyma and white matter. Thus the presence of ACT appears to be related to the response of astrocytes to the brain abnormalities seen in these conditions.

Adolescent↗