Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013080 (Down syndrome)
 14,180 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal thread protein (NTP) is a recently characterized molecule that is over-expressed in brains with Alzheimer's disease (AD) lesions. The present study encompasses a detailed analysis of NTP expression in AD compared with other neurodegenerative diseases and aged controls. Using a specific monoclonal antibody, NTP immunoreactivity was evaluated in 309 paraffin-embedded sections from 8 different regions of the frontal, parietal, and temporal lobes of 73 brains with AD, AD + Down's syndrome (DN), AD + Parkinson's disease (PD), PD dementia (PDD), aged controls, and disease controls with Huntington's disease, multi-infarct dementia, or schizophrenia. In 250 adjacent blocks of snap-frozen unfixed tissue the concentration of NTP (ng/mg of protein) was measured using a 3-site forward sandwich monoclonal antibody based immunoradiometric assay (M-IRMA). Immunohistochemical studies demonstrated that brains with AD, AD + PD, and AD + DN contained significantly higher densities of NTP immunoreactive neurons and more frequent immunostaining of neuropil and white matter fibers compared with PDD and aged controls (both P < 0.001) which had few or no AD lesions. In addition, the overall mean concentrations of NTP in AD, AD + PD, and AD + DN were significantly higher than in PDD and aged controls (P < 0.005). Greater degrees of NTP immunoreactivity and higher concentrations of the protein in cerebral tissue were significantly correlated with AD diagnosis and abundant neurofibrillary tangles (P < 0.005). The findings suggest that NTP over-expression may serve as a marker for the type of neuronal degeneration that occurs in AD.
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PMID:Neuronal thread protein over-expression in brains with Alzheimer's disease lesions. 148 53

Neuronal cells from murine trisomy 16 fetuses have increased levels of class I MHC H-2Kk. To determine whether this increased level of H-2Kk protein product resulted from an increased synthesis of mRNA, a 33 base antisense cDNA probe complementary to a region in exon 2 of the H-2Kk sequence (nucleotide 392-424) was synthesized. This probe was used to examine, by in situ hybridization and immunohistochemistry, the neural distribution of H-2Kk mRNA and protein product. A marked elevation of the H-2Kk mRNA and protein were localized in mts16 neuronal populations that were susceptible to dysgenesis. The results implicate the expression of the H-2Kk in the neuropathology of mts16 and its human counterpart, Down syndrome.
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PMID:Relationship between the neural dysgenesis and increased production of class I MHC H-2Kk mRNA and protein in neurons of murine trisomy 16 fetuses. 188 45

Neuronal cytoskeletal abnormalities may be a common factor in the neurobiologic causes of diverse forms of mental deficiency including Down's syndrome (DS). MabN210 which recognizes the 210 kDa subunit of neurofilaments was applied to sections of autopsy-derived DS and control central nervous system tissue. The findings included precocious and possibly aberrant neurofilament antigen expression during the first few months of life in DS cerebellar basket cell axons. Staining of central white matter tracts revealed an increased caliber of immunoreactive axons suggesting a widespread abnormality in mabN210 antigen expression in DS neurons. This abnormal regulation of normal neurofilament antigenic epitopes may be causally related to the development of Alzheimer's disease in DS.
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PMID:Down's syndrome. Precocious neurofilament antigen expression. 295 66

Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid beta A4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral sclerosis. It is possible that in these neurodegenerative disorders affected neurons either take up or synthesize lactotransferrin to an abnormally elevated rate. An excessive accumulation of lactotransferrin, as well as transported iron and aluminum, may lead to a cytotoxic effect resulting in the formation of intracellular lesions and neuronal death.
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PMID:The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis. 795 73

The high degree of overlap in the neuropathologic outcome of Alzheimer's disease (AD), Down's Syndrome (DS), and coronary heart disease suggest a possible interrelationship. The pattern of hippocampal and cortical intraneuronal beta A4 immunoreactivity is strikingly similar in AD, DS, coronary heart disease, and two separate animal models of coronary heart disease. Cells in fascia dentata and large cortical neurons were beta A4 immunodecorated in half the AD and DS subjects studied. Similar neuronal staining occurred in half the age-matched coronary heart disease subjects, but was absent in each nonheart disease control investigated. Analogous accumulations of neuronal beta A4 immunoreactivity were induced in rabbit brain by dietary administration of high cholesterol, and this effect could be reversed by regression of the experimental diet. Decreased density (p < 0.05) and cellular staining intensity occurred after 2 weeks of control diet following 8 weeks of high cholesterol. Microgliosis accompanied the accumulation of beta A4 immunoreactivity in the cholesterol-fed rabbits and persisted after regression of the diet and decreases in neuronal beta A4 immunoreactivity. An identical pattern of neuronal beta A4 immunoreactivity was induced in the brains of adolescent pigs after acute ligation of the left anterior descending coronary artery (LAD) compared to surgical and anesthetic controls. The mean number of beta A4 immunoreactive neurons was significantly increased (p < 0.05) in the cortex and hippocampus of pigs with a ligated LAD compared to both control groups. Increased density and intensity of neuronal beta A4 immunoreactivity induced by ligation of the LAD was commensurate with the severity of the decreased cardiac output in the LAD group, but not in the anesthetic control groups with decreased cardiac output. The incidence of ALZ-50 (A68) immunoreactive neurons also increased in the ligated pigs compared to both control groups. The data suggest a neuronal origin of beta A4 immunoreactive peptide(s), which can be cleared from the brain by microglia after severe accumulation is induced. This could indicate that reduced clearance of beta-APP metabolic by-products could contribute to a metabolic backlog and redirection of peptide processing by microglia to extracellular deposition. Neuronal accumulation of beta A4 immunoreactivity could be due to the effect of circulating factors on brain function in both animals models. It is likely that animal models of coronary heart disease may be useful in disclosing the mechanism of SP formation and induction of ALZ-50 immunoreactivity irrespective of their pathoclinical significance.
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PMID:Intraneuronal beta-amyloid immunoreactivity in the CNS. 874 11

Neuronal thread proteins (NTP) are a group of immunologically related molecules expressed in brain and neuroectodermal tumor cell lines. NTP gene expression is up-regulated and NTP molecules accumulate in Alzheimer's disease (AD) brains, pathological states associated with regenerative neuritic sprouting, and during brain development. To investigate the role of NTP over-expression in AD, we examined NTP immunoreactivity in brains from differently aged individuals with Down syndrome, since patients with Down syndrome nearly always develop AD neuropathology and dementia. Using SMI monoclonal antibodies to neurofilament protein, we detected age-associated increases in neurofilament immunoreactive (SMI-positive) neurites in Layers I and II of the cerebral cortex beginning at 1 year of age, followed by SMI-positive neurofibrillary tangles beginning at age 5 years, and then SMI-positive plaques beginning in the third decade. Increased NTP immunoreactivity in Down syndrome brains began in the second decade, prior to establishment of widespread AD neurodegeneration (Down syndrome + AD), and at an age when low-level or absent NTP expression was observed in control brains. Analysis of SDS and Triton X-100-treated histological sections and tissue extracts demonstrated that a largely insoluble, denaturation-resistant form of NTP accumulates in both Down syndrome + AD and AD brains. The findings provide further evidence that abnormal NTP expression and accumulation in brain may be an early marker of AD neurodegeneration in Down syndrome.
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PMID:Developmental patterns of neuronal thread protein gene expression in Down syndrome. 886 67

Recent studies, showing that cell cycle-related nuclear proteins p105 and Ki-67 are associated with Alzheimer's disease (AD)-related cytoskeletal pathology, suggested that these proteins, in addition to their functions in regulating the cell cycle, may have more specialised functions in the adult nervous system. In order to test this hypothesis we studied the expression of the cell cycle-related proteins Ki-67, pCNA and p53 in the hippocampi of 33 subjects, including some with AD or other neurodegenerative disorders and some with no neurological disease. By immunohistochemistry we found nuclear expression of Ki-67 in all subregions of the hippocampus, with the highest levels in the dentate gyrus. Both neurons and glial cells expressed this protein. The proportion of cells positive for Ki-67 and the distribution pattern varied considerably depending on the pathological diagnosis. Neuronal nuclear expression of Ki-67 was increased in AD but was also elevated in young Down's syndrome subjects and in those with Pick's disease. Expression of this protein was therefore not AD-specific. We did not find nuclear pCNA or p53 expressed in our patient groups. Contrary to previous studies AD-type neurofibrillary tangles were not labelled with any of the cell cycle markers used. The presence of nuclear Ki-67 expression indicates that some hippocampal neurons are not in the quiescent G0 phase but have re-entered the cell cycle. The absence of nuclear pCNA or p53 suggests that the cycle is arrested in G1. The significance of our findings and their relationship to the production of neurodegenerative cell death via an apoptotic mechanism are discussed.
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PMID:Expression of cell division markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions. 960 Jun 3

Neuronal inclusions with bundles of abnormal filaments made of tau polymers are found in numerous diseases with neurofibrillary degeneration. Tau proteins are the basic components of paired helical filaments (PHF) in Alzheimer's disease (AD), and are abnormally phosphorylated. A disease-specific phosphorylation site at serine422 was demonstrated on PHF, but not on tau proteins from biopsy-derived brain samples. In the present study, we report the characterization of a polyclonal antibody (988) against the serine422 phosphorylation site. By using biochemical and immunohistochemical methods, we confirmed that it is not found on tau proteins from biopsy- or autopsy-derived control samples, and we investigated the presence of this epitope on tau proteins in several neurodegenerative disorders, including AD, Down syndrome (DS), Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), postencephalitic parkinsonism (PEP) and Pick's disease (PiD). By Western blotting, antibody 988 labeled the characteristic tau triplet (tau 55, 64, 69) in AD, DS, Guamanian ALS/PDC and PEP. PSP and CBD exhibited their typical tau doublet (tau 64, 69), whereas the doublet tau 55 and 64 was detected in PiD. In all of these neurodegenerative disorders, antibody 988 clearly labeled NFT and dystrophic neurites, as well as Pick bodies in PiD cases, whereas no staining was observed in control cases. These data indicate that phosphorylation of serine422 on tau proteins is a common feature among neurodegenerative disorders and is therefore not specific of AD. Moreover, phosphorylation of this epitope permits the distinction between normal tau proteins and pathological tau proteins.
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PMID:Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration. 1009 Jun 68

Neuronal loss, synaptic disconnection and neuritic sprouting correlate with dementia in Alzheimer's disease (AD). Nitric oxide (NO) is an important synaptic plasticity molecule generated by nitric oxide synthase (NOS) oxidation of a guanidino nitrogen of L-arginine. Experimentally, the NOS III gene is modulated with neuritic sprouting. In a previous study, NOS III expression was found to be abnormal in cortical neurons, white matter glial cells, and dystrophic neurites in AD and Down syndrome brains. The present study demonstrates the same abnormalities in neuronal and glial NOS III expression with massive proliferation of NOS III-immunoreactive neurites and glial cell processes in other neurodegenerative diseases including: diffuse Lewy body disease, Pick's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple system atrophy, and Parkinson's disease. However, each disease, including AD, was distinguished by the selective alterations in NOS III expression and sprouting in structures marred by neurodegeneration. Double label immunohistochemical staining studies demonstrated nitrotyrosine and NOS III co-localized in only rare neurons and neuritic sprouts, suggesting that peroxynitrite formation and nitration of growth cone proteins may not be important consequences of NOS III enzyme accumulation. The results suggest that aberrant NOS III expression and NOS III-associated neuritic sprouting in the CNS are major abnormalities common to several important neurodegenerative diseases.
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PMID:Neuritic sprouting with aberrant expression of the nitric oxide synthase III gene in neurodegenerative diseases. 1020 79

Neuronal loss is prominent in Alzheimer's disease (AD), and its mechanisms remain unresolved. Apoptotic cell death has been implicated on the basis of studies demonstrating DNA fragmentation and an up-regulation of proapoptotic proteins in the AD brain. However, DNA fragmentation in neurons is too frequent to account for the continuous neuronal loss in a degenerative disease extending over many years. Furthermore, the typical apoptotic morphology has not been convincingly documented in AD neurons with fragmented DNA. We report the detection of the activated form of caspase-3, the central effector enzyme of the apoptotic cascade, in AD and Down's syndrome (DS) brain using an affinity-purified antiserum. In AD and DS, single neurons with apoptotic morphology showed cytoplasmic immunoreactivity for activated caspase-3, whereas no neurons were labeled in age-matched controls. Apoptotic neurons were identified at an approximate frequency of 1 in 1100 to 5000 neurons in the cases examined. Furthermore, caspase-3 immunoreactivity was detected in granules of granulovacuolar degeneration. Our results provide direct evidence for apoptotic neuronal death in AD with a frequency compatible with the progression of neuronal degeneration in this chronic disease and identify autophagic vacuoles of granulovacuolar degeneration as possible means for the protective segregation of early apoptotic alterations in the neuronal cytoplasm.
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PMID:Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer's disease. Evidence for apoptotic cell death. 1055 Mar 1


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