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Query: UNIPROT:P06889 (Mol)
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Based on a suspected role of the immune system in the pathophysiology of Alzheimer's disease (AD) and the new discoveries of neuroimmune networks, the investigation of certain neuroimmune markers was performed in AD patients, healthy controls, and disease controls. In agreement with our previous immunological research on AD, the assessment of additional immune parameters revealed abnormalities of both cellular and humoral immunity in several AD patients. These include: 1. Enhanced production of cytokines, such as interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-6 (IL-6); 2. Increase plasma level of CD8-positive lymphocyte derived soluble CD8 (sCD8) antigen; and 3. Increased incidence of autoantibodies to brain myelin basic protein (MBP) and thymic cells. As analyzed by flow cytometry and enzyme immunoassay, the peripheral blood immunocytes from AD patients showed a significant increase in the expression of the brain-derived S-100 protein. In the cell proliferation assay, the blood immunocytes from healthy subjects responded to stimulation with beta-amyloid protein (beta AP), but this response was absent in AD patients. The initial results of our research suggest that the studies of specific markers of the neuroimmune axis may be potentially important for the new development of diagnostic and therapeutic strategies for AD.
Mol Neurobiol
PMID:Studies of neuroimmune markers in Alzheimer's disease. 753 89

The beta-amyloid peptide (beta AP), a 39 to 43 residue peptide, is the major component of Alzheimer plaques. Using circular dichroism spectroscopy, titration calorimetry, and analytical ultracentrifugation we have analyzed the self-association of beta AP(1-40) in aqueous solution and the binding of beta AP(1-40) to negatively charged lipid vesicles. The CD spectra of both aggregation and membrane binding are characterized by an isodichroic point at 212 nm, indicating a simple two-state equilibrium for both cases. In aqueous solution beta AP(1-40) exhibits a reversible, concentration-dependent random coil<-->beta-structure transition which can be described by a cooperative aggregation model with an association constant of s = 1.05 x 10(4)M-1 and a nucleation parameter of sigma = 0.012. A similar conformational change is observed upon addition of lipid. At a given peptide concentration, the addition of negatively charged, small unilamellar vesicles also induces a conformational change from a random coil conformation to a conformation with 40 to 60% beta-structure. The binding isotherm can be measured with high sensitivity titration calorimetry. It is approximately linear in the initial binding phase and exhibits an apparent saturation behaviour. The apparent binding constant decreases with concentration from Kapp approximately 2100 M-1 at low concentration to 700 M-1 at the highest concentration measured. Peptide penetration into the lipid membrane and peptide aggregation at the membrane surface are proposed as possible mechanisms to explain the lipid-induced random coil<-->beta-structure transition.
J Mol Biol 1995 Oct 06
PMID:Self-association of beta-amyloid peptide (1-40) in solution and binding to lipid membranes. 756 79

Genetic linkage studies have provided significant evidence that a major gene defect, AD3, for familial early-onset Alzheimer's disease (EOAD) is located at chromosome 14q24.3, between the short tandem repeat (STR) markers D14S52 and D14S53 defining a genetic size of 22.7 cM for the AD3 candidate region. We constructed a physical map of the AD3 region using yeast artificial chromosomes (YACs) selected from both the CEPH and megaCEPH YAC libraries using the AD3 linked STR markers as well as new sequence-tagged sites (STSs) designed based on YAC terminal sequences. The YAC map is contiguous in the region between D14S258 and D14S53, a region of 8.2 cM, and has an estimated physical size of 4-8 Mb. The YAC contig map was used as a framework to localize three known genes, a pseudogene and two brain expressed sequence tags (ESTs). Linkage analysis studies in two Belgian chromosome 14 EOAD families AD/A and AD/B, identified obligate recombinants in family AD/A with D14S289 and D14S61 reducing the genetic size of the candidate AD3 region substantially. The minimal AD3 candidate region measured 6.4 cM on the genetic map and is contained within six overlapping megaCEPH YACs that covered a physical distance estimated between 2 and 6 Mb. These YACs as well as other YACs in the YAC contig map are valuable resources in gene cloning efforts or genomic sequencing experiments aiming at isolating the AD3 gene.
Hum Mol Genet 1995 Aug
PMID:Genetic and physical characterization of the early-onset Alzheimer's disease AD3 locus on chromosome 14q24.3. 758 74

Previous studies have shown that beta-amyloid (A beta) peptides are neurotoxic. Recent data suggest that neurons undergoing A beta-induced cell death exhibit characteristics that correspond to the classical features of apoptosis, suggesting that these cells may initiate a program of cell death. This chapter explores the criteria and precautions that must be applied to evaluate mechanisms of cell death in vitro and in vivo, discusses the evidence supporting an apoptotic mechanism of cell death in response to A beta in cultured neurons, and describes potential correlations for these findings in the Alzheimer's disease brain. In addition, cellular signaling pathways that may be associated with apoptosis in response to A beta are examined, and support for apoptosis as a mechanism of cell death for other neurodegeneration-inducing stimuli (e.g., oxidative injury) is described. The connection of multiple stimuli that induce neuronal cell death to an apoptotic mechanism suggests that apoptosis could play a central role in neurodegeneration in the brain.
Mol Neurobiol 1995 Feb
PMID:A potential role for apoptosis in neurodegeneration and Alzheimer's disease. 759 31

1. The amyloid precursor protein (APP) is widely distributed among eukaryotic cells, however, its precise role in cellular functioning is not fully clarified. APP is glycoprotein membrane constituent and it may facilitate membrane associated functions. 2. The aim of the present study was to examine the possibility that APP may play a role in mediating cellular trophic responses. The methods made use of an antisense oligonucleotide that was prepared to the 5' terminus of APP and shown specifically to reduce the level of APP isoforms. 3. In sequential mixing experiments it was observed that the APP antisense oligonucleotide did not significantly modify the trophic response of PC12 cells pretreated with nerve growth factor (NGF). However, pretreatment of cells with the antisense oligonucleotide diminished NGF-induced increases in cellular size and neurite length. 4. These observations suggest that APP may play a role in modulating the trophic response. The combined use of APP antisense oligonucleotides and neurotrophic agents may find clinical utility in the treatment of Alzheimer-type dementia since it is known that NGF normally causes increases in APP levels.
Cell Mol Neurobiol 1994 Oct
PMID:Modulation of the PC12 cell response to nerve growth factor by antisense oligonucleotide to amyloid precursor protein. 762 5

In order to test the hypothesis that allelic variation within the Amyloid Precursor Protein (APP) gene influences susceptibility to common forms of Alzheimer's disease (AD) we screened the entire coding, promoter and 3' untranslated sequences of the APP gene for DNA variations in 30 unrelated patients and eight controls with probable AD by a combination of RT-PCR PCR and chemical cleavage mismatch analysis. Although we were unable to detect commonly occurring allelic variants, we were able to detect a novel mutation within the APP gene in one individual with late-onset AD. This mutation resulted in the substitution of a tryptophan residue for an arginine residue at codon 328 within exon 7 which encodes the so-called protease inhibitor domain of the 751 residue APP isoform. However, the pathological significance of this mutation is uncertain as neither this, nor any other mutation occurring within exon 7 of the APP gene was found in any of a further 102 AD patients and 86 age-matched controls. In conclusion, it is unlikely that susceptibility to AD results from commonly occurring allelic variants of the APP gene and it is even less probable that mutations within exon 7 of the APP gene are important risk factors for late-onset AD.
Hum Mol Genet 1995 May
PMID:No evidence that common allelic variation in the Amyloid Precursor Protein (APP) gene confers susceptibility to Alzheimer's disease. 763 45

To further investigate the role of calbindin D28k in Alzheimer's disease (AD); hippocampus, superior temporal gyrus and cerebellum from control and AD cases were examined by quantitative in situ hybridization. We report here a decrease in CaBD28k mRNA in the CA2 region of AD hippocampus compared to control subjects. There were no significant differences between AD and control subjects in the other regions studied.
Brain Res Mol Brain Res 1995 Jun
PMID:Calbindin D28k mRNA in hippocampus, superior temporal gyrus and cerebellum: comparison between control and Alzheimer disease subjects. 763 86

1. Aluminum (Al) has been implicated in neurotoxic syndromes in several conditions, including Alzheimer's disease (AD). The developmental stage of the mammalian brain most susceptible to Al was determined in rabbits systematically exposed to Al during the prenatal, postnatal, or second month or for 1 month as adults or as aged subjects. Eyeblink reflex classical conditioning showed an Al-induced learning deficit only in the adult and aged rabbits. 2. 4-Aminopyridine, which was reported to improve learning in AD subjects, attenuated the Al-induced learning deficit. 3. Conditioned eyeblink acquisition is slower in AD subjects than controls, supporting the Al-loaded rabbit as a model of some AD effects. 4. To determine if the Al-loaded rabbit modeled the AD cholinergic deficit, acetylcholine (Ach) overflow was measured in rabbit hippocampus using microdialysis. Aluminum pretreatment reduced basal and potassium-stimulated Ach overflow compared to controls. 5. Acetylcholine overflow increased as control rabbits acquired the conditioned eyeblink reflex, then subsequently decreased, although conditioned eyeblink performance continued. In contrast, Al-loaded rabbits showed a delay in conditioned eyeblink acquisition and greatly attenuated Ach overflow. The Al-induced attenuation of Ach overflow may contribute to the Al-induced learning deficit. 6. Brain Al entry was studied using microdialysis of blood, brain, and lateral ventricle. Aluminum rapidly entered the brain and lateral ventricle. Frontal cortical Al was greater than lateral ventricular Al, suggesting that Al primarily enters the brain through the cerebral microvasculature. 7. The brain/blood Al ratio was always significantly less than 1. This ratio was influenced by the Al form administered, brain site and animal species. Thus, there appears to be an active process moving Al out of brain extracellular fluid (ECF). 8. Brain and blood dialysate Ach concentrations were not different after cyanide addition to the dialysate, supporting the conclusion that an active process moves Al out of brain ECF.
Cell Mol Neurobiol 1994 Dec
PMID:Studies of aluminum neurobehavioral toxicity in the intact mammal. 764 Dec 37

Infrared spectroscopy which has traditionally been utilized by chemists and physicists for characterization and identification of the structural properties of chemical compounds is now becoming more relevant as a biodiagnostic tool. Recent reports suggest that arthritis and Alzheimer's disease can be diagnosed by using this technique. Changes associated with these diseases diagnosable with this technique are generally overt. In this study we have used 'Fourier transform infrared spectroscopy' (FT-IR) to analyze subtle changes in composition and structure of lipids and proteins in lung tissue, bronchoalveolar lavage and purified lamellar body fraction of mice exposed to methylmercury. Infrared measurements were made in attenuated total reflection mode using the Split Pea (Harrick Scientific Corporation, USA). Mice were treated with 4 doses of methylmercuric chloride (15 mg/kg body weight/dose), and control animals received an equivalent volume of physiological saline. Comparison of the control and experimental spectra revealed alterations in the intensities and frequencies of vibrational modes of lipids following methylmercury exposure. Results indicate that FT-IR spectral analyses may be a valuable tool for detecting subtle variations in biological components associated with drug exposure to lungs and, in particular may be very useful for assessing changes in bronchoalveolar lavage.
Mol Cell Biochem 1995 Apr 12
PMID:FT-IR spectroscopy of methylmercury-exposed mouse lung. 765 80

We have used nonisotopic in situ hybridization techniques with biotinylated junctional oligonucleotide probes to study expression of amyloid precursor protein (APP) 695 and 751 mRNA in the hippocampal formation of Alzheimer's disease. Both mRNAs are strongly expressed in neurons of the hippocampal formation, particularly in the dentate gyrus granule cells and the pyramidal neurons of CA3. The patterns of expression of neither APP695 nor APP751 mRNA correlate well with the stereotyped topography of neurofibrillary tangles or senile plaques, which occur primarily in CA1 and subiculum. We double-labeled in situ sections with immunohistochemical reagents for neurofibrillary tangles or senile plaques. Neurons that contain neurofibrillary tangles continue to express APP mRNA. The level of APP695 and APP751 was measured semiquantitatively by optical density measurements in neurons that were close to (within 25 microns) or father from a senile plaque (more than 100 microns). There was no increase in expression in neurons in the immediate microenvironment of senile plaques. Our results suggest that no major change in distribution or type of APP mRNA accompanies neurofibrillary tangle or senile plaque development.
Brain Res Mol Brain Res 1993 May
PMID:Nonisotopic in situ hybridization of amyloid beta protein precursor in Alzheimer's disease: expression in neurofibrillary tangle bearing neurons and in the microenvironment surrounding senile plaques. 768 84


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