The key protein in Alzheimer's disease, the amyloid precursor protein (APP), is a ubiquitously expressed copper-binding glycoprotein that gives rise to the A␤ amyloid peptide. Whereas overexpression of APP results in significantly reduced brain copper levels in three different lines of transgenic mice, knock-out animals revealed increased copper levels. A provoked rise in peripheral levels of copper reduced concentrations of soluble amyloid peptides and resulted in fewer pathogenic A␤ plaques. Contradictory evidence has been provided by the efficacy of copper chelation treatment with the drug clioquinol. Using a yeast model system, we show that adding clioquinol to the yeast culture medium drastically increased the intracellular copper concentration but there was no significant effect observed on zinc levels. This finding suggests that clioquinol can act therapeutically by changing the distribution of copper or facilitating copper uptake rather than by decreasing copper levels. The overexpression of the human APP or APLP2 extracellular domains but not the extracellular domain of APLP1 decreased intracellular copper levels. The expression of a mutant APP deficient for copper binding increased intracellular copper levels severalfold. These data uncover a novel biological function for APP and APLP2 in copper efflux and provide a new conceptual framework for the formerly diverging theories of copper supplementation and chelation in the treatment of Alzheimer's disease.The amyloid precursor protein (APP) 1 of Alzheimer's disease (AD) is a ubiquitously expressed copper-binding glycoprotein that gives rise to the A␤ amyloid peptide (1). The APP paralogs and orthologs demonstrate a significant evolutionary change in the function of the N-terminal copper-binding domain (CuBD). In higher species, CuBD has a gain-in activity toward promoting Cu(II) reduction (2, 3).Copper deprivation strongly down-regulates APP gene expression and reduces APP levels (4). Animal model systems revealed that APP is actively involved in balancing copper concentrations in vivo. Whereas overexpression of APP results in significantly reduced brain copper levels in three different lines of transgenic mice, APP23, Tg2576, and TgCRND8 (5-7), conversely, APP and APLP2 knock-out mouse revealed increased copper levels in cerebral cortex and liver (8). Whereas the relevance of a disturbed metal ion homeostasis in Alzheimer's disease is presently unclear (9 -11), studies in two different transgenic mouse models convincingly demonstrate that a rise in peripheral copper levels reduced soluble A␤ peptide levels (5) and the number of A␤ plaques (7). In a mammalian cell line, increasing intracellular copper levels attenuated APP processing into A␤ and stimulated secreted APP levels (5, 12). This finding demonstrates that copper-binding to APP alters the turnover of brain APP and concomitantly offers an alternative therapeutic intervention. Based on earlier observations that copper and chelators have an effect on amyloid fibril formation (13), the Cu,Zn chelat...

␤-Site APP-cleaving enzyme (BACE) is a membranebound aspartyl protease with no strict primary preference for cleavage. The molecular mechanisms that link the ␥-secretase multicomponent amyloid precursor protein (APP) processing complex to biochemical properties of BACE generating the N terminus of the amyloid ␤-peptide have not, as yet, been identified. We found that in human brain tissue, BACE occurred as a dimer. The overall stability of the BACE homodimer was based on intermolecular interactions that were not affected by high salt, nonionic detergents or reducing conditions. BACE homodimers could only partially be separated even under strong denaturing conditions and revealed dramatic differences in the surface charge distribution compared with the monomer. In contrast, the soluble ectodomain of truncated BACE revealed a seemingly lower avidity to the prototypic aspartate protease inhibitor pepstatin and exclusively occurred in the monomeric form. Immunocytochemical studies colocalized APP and BACE in the plasma membrane of cells expressing endogenous levels of BACE and overexpressing APP. In cells that were cotransfected with APP and a putative active site D289A mutant of BACE, colocalization persisted. Remaining enzyme activity was found to be attributable to the mutant protease. Accordingly, inactivation of the carboxyl-terminal active site motif of BACE without an impairment of overall enzyme activity suggests that the enzyme may act as a dimer. Thus, homodimerization of BACE may help the enzyme to acquire specific mechanisms to associate with its substrates to exert catalytic activity.The amyloid precursor protein (APP) 1 of Alzheimer's disease is the only source of the amyloid peptide (A␤), the major constituent of the characteristic amyloid plaques (1-3). APP is part of a superfamily from which 16 homologous amyloid precursor-like proteins and APP species homologues are derived (4, 5). APP and amyloid precursor-like proteins are substrates for two proteolytic activities designated ␤-secretase and ␥-secretase (6 -8). The molecular apparatus for the ␥-site cleavage is quite complex and requires the presence of presenilin-1, which is believed to be the ␥-secretase itself (9 -11).The ␤-site APP-cleaving enzyme (BACE) initiates A␤ formation by cleaving at the amino terminus to generate the truncated ectodomains of APP and amyloid precursor-like proteins (8,(12)(13)(14)(15). In addition to APP family members, other substrates discovered for BACE are the sialyltransferase ST6Gal-I, the P-selectin glycoprotein ligand-1, and A␤ itself (16 -18). No A␤ peptides can be detected in mice with a homozygous deletion of bace, demonstrating the essential role in the generation of this peptide (19,20). On the other hand, the A␤ load correlates with increased ␤-secretase activity in sporadic Alzheimer's disease patients (21,22). The elevated BACE mRNA and protein expression in vivo is not due to mutations in the ORF but is rather suggested to occur by a change in the translation efficiency (23,24).BACE is synthesized as a...

BackgroundPostural development progresses through a series of stages (growth spurts, development of balance and coordination, postural stability) which occur when children are at school age. The reduction in the level of physical activity, increased body weight, overloaded school bags, asymmetry of the backpack straps, the method of putting on and taking off the backpacks and increased usage of electronic devices have negative side effects such as bad body posture habits.MethodsA prospective cohort study in the group of 155 pupils at early school age 7–9 years old has been conducted. Examinations have been conducted twice: first, at the beginning of the school year (initial examination) and second – after 10–11 months (final examination). Age, gender, BMI, weight of school bag carried to school and the length of straps have been assessed. Body posture measurement (using Adams’ test), the evaluation of the plumb line deflection from the gluteal cleft, the angle values of kyphosis and lordosis (according to Dobosiewicz methodology) and the pelvis and shoulder blades position (using a ruler and pediscoliometer) have been also measured.ResultsThe mean weight of a school bag in the initial study was 6.3 ± 0.8 (range between 4,7 and 9 kg). A tendency to carry slightly heavier school bags was noted in boys (6.7 vs. 5.9 kg; p = 0,00001). This tendency has linearly changed with age (R = 0.68; p < 0,001). In 3.2% of all school bags of children, weights exceeded norms with regard to the weight of the pupil. The increase of torso rotation exceeding norms was observed in 35.3% of girls (mean 2.7 ± 1.2) and in 60.9% of boys (mean 2.3 ± 1.3). The increase of kyphosis angle was noted in 48.5% of girls and in 36.8% of boys. The difference of straps length had a significant influence on the increase of rotation in upper thoracic spine, thoracolumbar junction and it also had influence on the decrease of lumbar lordosis in the group of girls.ConclusionsDifferences in the weight of school bags after one school year have influenced changes in body posture abnormalities, especially in rotation parameters. Backpack straps asymmetry was noticeably stronger in the group of girls and the difference between braces may have an impact on some posturometric parameters. Lack of proper backpack lifting skills tends to create programs and training systems in this regard.

BackgroundThis study examined the association between the physical work environment and physiological performance measures, physical activity levels and metabolic parameters among German civil servants. A main focus in this study was to examine the group differences rather than measuring the absolute values in an occupational group.MethodsWe prospectively examined 198 male German civil servants (97 firefighters [FFs], 55 police officers [POs] and 46 sedentary clerks [SCs]). For each parameter, the groups were compared using a linear regression adjusted for age.ResultsThe 97 FFs showed a similar maximal aerobic power (VO2max l/min) of 3.17±0.44 l/min compared with the POs, who had a maximal aerobic power of 3.13±0.62 l/min (estimated difference, POs vs. FFs: 0.05, CI: -0.12-0.23, p=0.553). The maximal aerobic power of the FFs was slightly higher than that of the SCs, who had a maximal aerobic power of 2.85±0.52 l/min (-0.21, CI: -0.39-0.04, p=0.018 vs. FFs). The average physical activity (in metabolic equivalents [METS]/week) of the FFs was 3818.8±2843.5, whereas those of the POs and SCs were 2838.2±2871.9 (-808.2, CI: 1757.6-141.2, p=0.095) and 2212.2±2292.8 (vs. FFs: -1417.1, CI: -2302-531.88, p=0.002; vs. POs: -2974.4, CI: -1611.2-393.5, p=0.232), respectively. For the FFs, the average body fat percentage was 17.7%±6.2, whereas it was 21.4%±5.6 for the POs (vs. FFs: 2.75, CI: 0.92-4.59, p=0.004) and 20.8%±6.5 for the SCs (vs. FFs: 1.98, CI: -0.28-4.25, p=0.086; vs. POs: -0.77, CI: 3.15-1.61, p=0.523). The average waist circumference was 89.8 cm±10.0 for the FFs, 97.8 cm±12.4 (5.63, CI: 2.10-9.15, p=0.002) for the POs, and 97.3±11.7 (vs. FFs: -4.89, CI: 1.24-8.55, p=0.009; vs. POs: -0.73, CI: -5.21-3.74, p=0.747) for the SCs.ConclusionsThe FFs showed significantly higher physical activity levels compared with the SCs. The PO group had the highest cardiovascular risk of all of the groups because it included more participants with metabolic syndrome; furthermore, the POs had an average of 2.75% higher body fat, lower HDL cholesterol values and higher waist circumferences compared with the FFs and higher LDL cholesterol values compared with the SCs. Our data indicate that sedentary occupations appear to be linked to obesity and metabolic syndrome in middle-aged men.

BackgroundThe treatment and prevention of the metabolic syndrome (MetS) is currently one of the major challenges in medicine. The impact of working conditions on metabolic risk has not been adequately studied. Our objective was to compare the prevalence of MetS and metabolic risk in two extremely different occupational groups: firefighters and office workers.MethodsA total of 143 male subjects (97 firefighters and 46 office workers) from Germany participated in the study. Anthropometric characteristics, metabolic risk parameters as well as laboratory parameters were collected. MetS was diagnosed according to criteria of the International Diabetes Federation.ResultsSedentary occupation showed a significant tendency towards obesity. Abdominal waist circumference was significantly greater in office workers than in firefighters [5.08 CI (1.44–8.71), p = 0.007]. Concerning metabolic risk factors, abnormal HDL, triglycerides, BMI, blood pressure and waist circumference values were more frequently found in office workers than in firefighters. The MetS was detected in almost 33 % of office workers as compared with only 14 % in firefighters (p = 0.015). Regarding MetS in an international comparison, the prevalence of MetS in German office workers was high and in firefighters it was extremely low.ConclusionsSedentary occupation as an office worker is associated with a high risk of MetS. Both groups need to be made aware of the metabolic risks, and health promoting concepts such as corporate sports activities or education in healthy nutrition need to be implemented to counteract the development of the MetS and cardiovascular risk factors.