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S L Wagner

Publications and source records attributed to S L Wagner.

At least 19 recordsLinked to original sources
PubMed2004

Clearance of Alzheimer's Abeta peptide: the many roads to perdition.

The amyloid hypothesis of Alzheimer's disease (AD) maintains that the accumulation of the amyloid beta protein (Abeta) is a critical event in disease pathogenesis. A great deal of both academic and commercial research has focused on the mechanisms by which Abeta is generated. However, investigations into the mechanisms underlying Abeta clearance have blossomed over the last several years. This minireview will summarize pathways involved in the removal of cerebral Abeta, including enzymatic degradation and receptor-mediated efflux out of the brain.

Alzheimer Disease↗
PubMed2001

Optimizing off-pump coronary artery bypass graft: technical and metabolic aspects.

PURPOSE: Our purpose was to determine if complete revascularization could be successfully performed off bypass in the majority of coronary artery bypass graft (CABG) patients. METHODS: Using a metabolic protocol and the Medtronic Octopus stabilizer device (Medtronic, Inc., Minneapolis, MN), 285 consecutive patients between July 1, 1997 and July 31, 1999 were successfully revascularized off pump via median sternotomy. A relative contraindication for off bypass CABG was cardiogenic shock. The metabolic protocol was designed to enhance systolic and diastolic cardiac function during surgery. RESULTS: Of 298 patients on whom we attempted off-pump revascularizations, 96% (285/298) were successful. The mean number of grafts per case was 3.3. The mean age of patients was 69.5 years, and 38% (109/285) were 75 years of age or older. Perioperative myocardial infarction (MI) occurred in two patients (0.7%) and operative mortality was 2.8% (8/285). Average Parsonnet score was 4.8. Cost savings were realized through minimal blood product utilization (average 1.5 units per case) and decreased cardiopulmonary bypass supplies. CONCLUSION: Complete revascularization can be performed off bypass in the majority of CABG patients. The concomitant use of the Octopus off-bypass technique with aggressive metabolic support ensures manual manipulation of a beating heart and results in a low incidence of postoperative complications and significant cost savings.

Adult↗
PubMed2000

Altruistic organizational citizenship behavior: context, disposition, and age.

The authors proposed employee age as moderating the structural stability of altruistic organizational citizenship behavior (OCB) with regard to the influence of context-relevant attitudes and dispositional variables. Analyses of peer ratings of altruistic OCB in a sample of 96 U.S. nurses showed that the contextual variables of job satisfaction, organizational commitment, and trust in management were germane for the younger participants. The dispositional variable of moral judgment was a unique predictor of altruistic OCB among the older participants.

Adult↗
PubMed2000

Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway.

Susceptibility to Alzheimer's disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and alpha2M, are all genetically associated with AD. In this study, we provide evidence for the involvement of the LRP pathway in amyloid deposition through sequestration and removal of soluble amyloid beta-protein (Abeta). We demonstrate in vitro that LRP mediates the clearance of both Abeta40 and Abeta42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble Abeta levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for Abeta, this work provides the first in vivo evidence that the LRP pathway may modulate Abeta deposition and AD susceptibility by regulating the removal of soluble Abeta.

Adult↗
PubMed1999

Reduced cerebrospinal fluid levels of alpha-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits.

The amyloid precursor protein undergoes proteolysis at several sites to yield a number of functionally relevant peptides, including beta-amyloid and the soluble amyloid precursor protein derivatives alpha-soluble amyloid precursor protein and beta-soluble amyloid precursor protein. beta-Amyloid is the primary constituent of senile plaques associated with Alzheimer's disease, while a-soluble amyloid precursor protein promotes synaptogenesis and plays a role in neuroprotective processes. We tested for age-related alterations in these amyloid precursor protein proteolytically derived peptides by measuring the levels of alpha-soluble amyloid precursor protein, total soluble amyloid precursor proteins (alpha- and beta-soluble amyloid precursor protein combined) and beta-amyloid in cerebrospinal fluid from three-, 13- and 23-month-old Fischer-344 rats. Western blot analysis using selective antibodies revealed 50% less total soluble amyloid precursor protein and a-soluble amyloid precursor protein in cisternal cerebrospinal fluid from 23-month-old rats compared with three- and 13-month-old animals. Mass spectrometric analysis indicated, however, that beta-amyloid in cerebrospinal fluid was not different between the three age groups. In a second group of young (five to six months of age) and aged (24-25 months of age) rats, spatial working and reference memory were assessed in a water maze followed by collection of cerebrospinal fluid. As a group, the aged rats consistently performed below the young rats in both working and reference memory tests. The aged rats also had 49% less cerebrospinal fluid alpha-soluble amyloid precursor protein than did their younger counterparts. There was a positive correlation (r= 0.52-0.57, P < 0.001) between performance in spatial memory tasks and cerebrospinal fluid alpha-soluble amyloid precursor protein in these young and aged rats. These results suggest that there is a positive association between cerebrospinal fluid levels of alpha-soluble amyloid precursor protein and cognitive performance in rats, and that alpha-soluble amyloid precursor protein may be involved in the spatial learning and memory changes that accompany ageing.

Aging↗
PubMed1997

Cerebrospinal fluid levels of alpha-secretase-cleaved soluble amyloid precursor protein mirror cognition in a Swedish family with Alzheimer disease and a gene mutation.

OBJECTIVE: To explore the relationship between possible biological markers of Alzheimer disease that are related to amyloid metabolism and mental functions. PARTICIPANTS: Twelve individuals from a Swedish family with Alzheimer disease and a double mutation at codons 670/671 of the amyloid precursor protein gene participated in the study. DESIGN: Cerebrospinal fluid levels of alpha-secretase cleaved soluble amyloid precursor protein (alpha-sAPP), total sAPP, and amyloid beta-peptide were correlated with data on multiple cognitive functions that covered the whole range of human performance. SETTING: The Alzheimer's Disease Research Centre, Department of Clinical Neuroscience, Section of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden. RESULTS: There were highly significant linear correlations between low levels of alpha-sAPP and poor performance on neuropsychological tests that assessed intelligence, verbal and visuospatial functions, memory, and attention. Within the group of nonmutation carriers, significant correlations were also obtained between the levels of alpha-sAPP and cognitive functions. A less striking association was seen between the levels of total sAPP and cognition. No association was found between the levels of amyloid beta-peptide and cognition. CONCLUSIONS: The strong relationship between alpha-sAPP levels and cognition in both patients with Alzheimer disease and normal-aging persons may imply that alpha-sAPP is involved in basic protective brain processes. Alternatively, less amyloid beta-peptide amounts are produced, leading to diminished plaque formation, when alpha-sAPP is generated.

Adult↗
PubMed1997

Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice.

Missense mutations in the beta-amyloid precursor protein gene (APP) co-segregate with a small subset of autosomal dominant familial Alzheimer's disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid (A beta) peptide and neurodegeneration are principal neuropathological hallmarks. To accurately examine the effect of missense mutations on APP metabolism and A beta production in vivo, we have introduced yeast artificial chromosomes (YACs) containing the entire approximately 400 kbp human APP gene encoding APP harboring either the asparagine for lysine and leucine for methionine FAD substitution at codons 670 and 671 (APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717 (APP(V7171)) or a combination of both substitutions into transgenic mice. We demonstrate that, relative to YAC transgenic mice expressing wild-type APP, high levels of A beta peptides are detected in the brains of YAC transgenic mice expressing human APP(K670N/M671L) that is associated with a concomitant diminution in the levels of apha-secretase-generated soluble APP derivatives. Moreover, the levels of longer A beta peptides (species terminating at amino acids 42/43) are elevated in YAC transgenic mice expressing human APP(V7171). These mice should prove valuable for detailed analysis of the in vivo effects of the APP FAD mutations in a variety of tissues and throughout aging and for testing therapeutic agents that specifically alter APP metabolism and A beta production.

Alzheimer Disease↗
PubMed1997

Clinicopathologic correlations of soluble amyloid beta-protein precursor in cerebrospinal fluid in patients with Alzheimer disease and controls.

The authors compared concentrations of soluble beta-amyloid protein precursor (s beta PP) in cerebrospinal fluid (CSF) in 45 patients diagnosed with probable Alzheimer disease (AD) and 26 normal older control volunteers. Soluble beta-amyloid protein precursor concentrations were measured in 125 CSF samples using an enzyme-linked immunosorbent assay. All subjects had Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Scale (CDRS) scores and assessment of disease duration. The s beta PP concentrations in CSF in the probable AD group (mean +/- SD = 493 +/- 268 micrograms/L) were decreased significantly compared with the age-matched control group (mean = 831 +/- 302 micrograms/L; p < 0.0001). In the probable AD group, MMSE scores correlated positively with s beta PP concentrations (correlation coefficient r = 0.53, p < 0.0001), and CDRS ratings and disease duration correlated inversely with s beta PP concentrations (r = -0.59, p < 0.0001 and r = -0.479, p = 0.0006, respectively). Although the decrease in CSF s beta PP from levels found in healthy elderly controls was significant in AD subjects, there was substantial overlap. In AD, CSF s beta PP was most reduced in patients in later stages of the disease. The s beta PP concentrations reflect disease severity, but utility in differential diagnosis has not been determined.

Aged↗
PubMed1995

Enhanced plasmin inhibition by a reactive center lysine mutant of the Kunitz-type protease inhibitor domain of the amyloid beta-protein precursor.

The Alzheimer's disease related protein, amyloid beta-protein precursor (A beta PP), contains a domain homologous to Kunitz-type serine protease inhibitors (KPI). The recombinant KPI domain of A beta PP is a potent inhibitor of coagulation factors XIa and IXa and functions as an anticoagulant in vitro. Here we report the expression, purification, and characterization of a reactive center lysine mutant of the KPI domain of A beta PP (KPI-Lys17). An expression plasmid for the KPI-Lys17 domain of A beta PP encoded amino acids 285-345 of the A beta PP cDNA containing a lysine substitution at arginine 17 in the KPI domain. The secreted 61-amino acid product was purified to homogeneity and functionally characterized. The protease inhibitory properties of the KPI-Lys17 domain were compared to those of the native KPI domain of A beta PP. Both KPI domains equally inhibited trypsin, chymotrypsin, and coagulation factors IXa and Xa. However, the KPI-Lys17 domain was an approximately 25-fold less effective inhibitor of coagulation factor XIa resulting in markedly less prolongation of the activated partial thromboplastin time compared to the native KPI domain of A beta PP. On the other hand, the KPI-Lys17 domain was an approximately 10- and 5-fold better inhibitor of plasmin in a chromogenic substrate assay and in a fibrinolytic assay, respectively, than the native KPI domain of A beta PP. Together, these studies suggest that the KPI-Lys17 domain has enhanced anti-fibrinolytic and diminished factor XIa inhibitory properties compared to the native KPI domain of A beta PP.

Amino Acid Sequence↗
PubMed1995

Decreased alpha-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer's disease.

The neuropathologic hallmarks of Alzheimer's disease (AD) are extracellular plaques and intracellular neurofibrillary tangles. A constituent of senile plaques in AD is beta-amyloid, a hydrophobic peptide of 39-43 amino acids and a fragment of the amyloid precursor protein (APP). APP can be metabolized by at least two pathways, one of which involves generation of soluble APP by an unidentified enzyme named alpha-secretase. This cleavage generates alpha-secretase-cleaved, soluble APP (alpha-sAPP), which in this investigation was measured by a new assay in cerebrospinal fluid (CSF) from members of a Swedish AD family with a pathogenic mutation at APP670/671 (ref. 2). Family members who carry the mutation and are diagnosed with AD had low levels of alpha-sAPP (160 +/- 48 ng ml-1), with no overlap compared with non-carriers (257 +/- 48 ng ml-1). Carriers of the presymptomatic mutation showed intermediate alpha-sAPP levels. Today there exists no antemortem marker in AD with sufficient sensitivity and specificity, but measurement of alpha-sAPP represents a new and promising diagnostic marker.

Adult↗
PubMed1994

Expression, purification, and characterization of the Kunitz-type proteinase inhibitor domain of the amyloid beta-protein precursor-like protein-2.

In this report we describe the use of the methylotrophic industrial yeast Pichia pastoris as a host system for the large scale production of the Kunitz-type proteinase inhibitor (KPI) domain of the amyloid beta-protein precursor-like protein-2 (APLP-2). The expression plasmid for the KPI domain of APLP-2 encoded amino acids 305-364 of the APLP-2 cDNA (Slunt et al. (1994) J. Biol. Chem. 269, 2637-2644). The secreted 60 amino-acid product was purified to homogeneity and biochemically characterized. Amino-acid sequencing of the expressed KPI domain of APLP-2 verified its integrity. The proteinase inhibitory properties of the KPI domain of APLP-2 were compared to those of the KPI domain of proteinase nexin-2/amyloid beta-protein precursor (PN-2/A beta PP). Both KPI domains potently inhibited trypsin and, to a lesser extent, chymotrypsin, plasmin, and coagulation factors XIa and IXa. However, the KPI domain of APLP-2 was a approximately 20-fold less effective inhibitor of coagulation factor XIa compared to the KPI domain of PN-2/A beta PP. Similarly, the KPI domain of APLP-2 was a less effective anticoagulant in coagulation based assays than the KPI domain of PN-2/A beta PP. These studies indicate that the KPI domains of PN-2/A beta PP and APLP-2 form a family of proteinase inhibitors although the former is a better inhibitor of factor XIa and a more potent anticoagulant than the latter.

Amino Acid Sequence↗
PubMed1994

Metabolism of the "Swedish" amyloid precursor protein variant in Madin-Darby canine kidney cells.

The 4-kDa beta-amyloid peptide (A beta), a major constituent of parenchymal amyloid deposits in Alzheimer's disease, is derived from larger amyloid precursor proteins (APP). We have examined the metabolism of APP in Madin-Darby canine kidney cells stably transfected with cDNA encoding either wild-type human APP-695 or human APP-695 that harbors the Swedish double mutation associated with familial early-onset Alzheimer's disease. Although approximately 90% of total soluble APP secreted from wild-type cells is secreted basolaterally following cleavage at the alpha-secretase site, soluble derivatives cleaved near or at the amino terminus of A beta (presumably the "beta-secretase" site) are preferentially secreted into the apical compartment of SWE cells. Concomitantly, levels of a specific A beta-containing carboxyl-terminal fragment are elevated in SWE cell lysates. Using domain-specific biotinylation and release assays, we failed to detect a beta-secretase-generated soluble derivative (APPs beta) released from the surface of SWE cells. However, APPs beta can be detected in SWE cell lysates, consistent with "beta-secretase" cleavage occurring in an intracellular compartment. Finally, we demonstrate that A beta is secreted into the basolateral compartment of SWE cells and that the majority of these A beta-related species contains an amino-terminal aspartate residue (+1).

Amino Acid Sequence↗
PubMed1994

Decreased levels of soluble amyloid beta-protein precursor are associated with Alzheimer's disease in concordant and discordant monozygous twin pairs.

We conducted immunochemical measurements of soluble amyloid beta-protein precursor (beta PP) in cerebrospinal fluid (CSF) from three monozygous twin pairs. Two of the twin pairs are discordant for Alzheimer's disease and one pair showed concordance for Alzheimer's disease, which was confirmed neuropathologically. All affected individuals displayed substantially lower levels of soluble beta PP in CSF compared with the unaffected individuals. There were no differences in total protein levels in CSF samples from the affected twins compared with those of the unaffected twins. These studies suggest that decreased soluble beta PP in CSF may reflect neuropathological processes in Alzheimer's disease involving beta PP.

Aged↗
PubMed1994

Chronic organophosphate exposure associated with transient hypertonia in an infant.

OBJECTIVE: A 12-week-old infant girl developed persistent hypertonicity of the extremities, and, at the age of 8 months, it was discovered that her home had been treated with an excessive application of the organophosphate insecticide diazinon 5 weeks prior to the onset of symptoms. An estimation of her daily diazinon dose and possible correlation with her disease was made. METHODS: Analyses were performed for residues of diazinon in the home and for metabolites of diazinon in the infant. The infant was removed from the home. RESULTS: Six months after application the remaining diazinon residue on the floor was 230 ng/cm2 vs 38 ng/cm2 expected immediately after a normal application. Vacuum cleaner dust contained 1700 parts per million of diazinon. The air contained 2.8 ng/m3. The infant's urine contained 60 parts per billion of diethylphosphate and 20 parts per billion of diethylthiophosphate which calculates to a diazinon dose of approximately 0.02 mg/kg/d. When the infant was removed from the home, muscle tone returned to normal shortly thereafter. CONCLUSIONS: The evidence for an association between organophosphate exposure and the sole de-velopment of hypertonicity without other signs of intoxication in an infant is presented. Physicians should consider organophosphate insecticide exposure as a possible cause of hypertonicity in infants.

Diazinon↗
PubMed1993

Co-distribution of protease nexin-1 and protease nexin-2 in brains of non-human primates.

The protease nexins are protease inhibitors which regulate key blood coagulation proteases and which appear to be involved in certain physiological and pathological processes in the brain. Protease nexin-1 (PN-1), a potent inhibitor of thrombin, can regulate processes on cultured neurons and astrocytes. Protease nexin-2 (PN-2), a potent inhibitor of coagulation factor XIa, is identical to the secreted form of the Alzheimer's amyloid beta-protein precursor. In the present studies, PN-1 and PN-2 were analyzed in different tissues of monkey using monoclonal antibodies for either quantitative immunoblotting or specific [125I]protease-binding assays. PN-1 was detected only in brain. PN-2 was most abundant in brain, followed by testis and to a lesser extent kidney. Other tissues examined including spinal cord, heart, pancreas, spleen, liver, lung and muscle were essentially devoid of both PN-1 and PN-2. Within the brain, the levels of PN-1 and PN-2 were highest in the parietal cortex and lowest in the cerebellum and brainstem. The thalamus and striatum contained intermediate amounts of both proteins. Aged Cebus monkey cerebral cortical tissue contained slightly lower levels of PN-1 than did the middle-aged or young monkey tissue. The co-distribution of PN-1 and PN-2 in brain, their relative abundance in brain cortex, and previous studies on their functions suggest that in the brain they may participate in the regulation of blood coagulation and cell growth and differentiation.

Amyloid beta-Protein Precursor↗