Amyloid -peptide is generated by two sequential proteolytic cleavages mediated by -secretase (BACE) and ␥-secretase. BACE was recently identified as a membrane-associated aspartyl protease. We have now analyzed the maturation and pro-peptide cleavage of BACE. Pulse-chase experiments revealed that BACE is posttranslationally modified during transport to the cell surface, which can be monitored by a significant increase in the molecular mass. The increase in molecular mass is caused by complex N-glycosylation. Treatment with tunicamycin and N-glycosidase F led to a BACE derivative with a molecular weight corresponding to an unmodified version. In contrast, the mature form of BACE was resistant to endoglycosidase H treatment. The cytoplasmic tail of BACE was required for efficient maturation and trafficking through the Golgi; a BACE variant lacking the cytoplasmic tail undergoes inefficient maturation. In contrast a soluble BACE variant that does not contain a membrane anchor matured more rapidly than full-length BACE. Pro-BACE was predominantly located within the endoplasmic reticulum. Propeptide cleavage occurred immediately before full maturation and trafficking through the Golgi.Alzheimer's disease is the most common age-dependent dementia. Pathologically Alzheimer's disease is characterized by the invariant accumulation of senile plaques (1). Senile plaques are predominantly composed of amyloid -peptide (A), 1 which is derived from the -amyloid precursor protein (APP) (2). APP is a type 1 transmembrane protein that maturates during its transport to the cell surface by several post-translational modifications including N-and O-glycosylation (3), phosphorylation (3-5), sulfation (3), and endoproteolysis (2). Upon trafficking to the cell surface, APP can be reinternalized and targeted to endosomes (6, 7). APP can recycle from endosomes back to the cell surface (8) or be targeted to lysosomes (7) for its final degradation (7,9). In polarized cells such as Madin-Darby canine kidney cells and hippocampal neurons, APP is transported to the basolateral compartment (10, 11) and to axons (12).During its transport to the cell surface, APP undergoes endoproteolytic cleavage. ␣-Secretase cleaves APP within its A domain leading to the secretion of APPs-␣ in biological fluids and conditioned medium of cultured cells (3, 13). -Secretase generates the N terminus of the A domain (2), and this cleavage can occur in direct competition to the ␣-secretase cut (14 -16). -Secretase cleavage appears to occur within the Golgi (15, 16) as well as during reinternalization within endosomes (6, 7). The membrane-bound C-terminal fragment generated by the -secretase cut is subsequently cleaved by the ␥-secretase, which results in the physiological generation and secretion of A (2).Interestingly, point mutations associated with familial Alzheimer's disease have been located at all three secretase cleavage sites, and these mutations pathologically affect endoproteolysis of APP (1).Recently major progress has been achieved in...
The assessment of treatment response in glioblastoma is difficult with MRI because reactive blood-brain barrier alterations with contrast enhancement can mimic tumor progression. In this study, we investigated the predictive value of PET using O-(2-18 F-fluoroethyl)-L-tyrosine ( 18 F-FET PET) during treatment. Methods: In a prospective study, 25 patients with glioblastoma were investigated by MRI and 18 F-FET PET after surgery (MRI-/FET-1), early (7-10 d) after completion of radiochemotherapy with temozolomide (RCX) (MRI-/FET-2), and 6-8 wk later (MRI-/FET-3). Maximum and mean tumor-to-brain ratios (TBR max and TBR mean , respectively) were determined by region-of-interest analyses. Furthermore, gadolinium contrastenhancement volumes on MRI (Gd-volume) and tumor volumes in 18 F-FET PET images with a tumor-to-brain ratio greater than 1.6 (T vol 1.6 ) were calculated using threshold-based volume-ofinterest analyses. The patients were grouped into responders and nonresponders according to the changes of these parameters at different cutoffs, and the influence on progression-free survival and overall survival was tested using univariate and multivariate survival analyses and by receiver-operating-characteristic analyses. Results: Early after completion of RCX, a decrease of both TBR max and TBR mean was a highly significant and independent statistical predictor for progression-free survival and overall survival. Receiver-operating-characteristic analysis showed that a decrease of the TBR max between FET-1 and FET-2 of more than 20% predicted poor survival, with a sensitivity of 83% and a specificity of 67% (area under the curve, 0.75). Six to eight weeks later, the predictive value of TBR max and TBR mean was less significant, but an association between a decrease of T vol 1.6 and PFS was noted. In contrast, Gd-volume changes had no significant predictive value for survival. Conclusion: In contrast to Gd-volumes on MRI, changes in 18 F-FET PET may be a valuable parameter to assess treatment response in glioblastoma and to predict survival time.
Glucose metabolism is reduced more than perfusion in the septal compared with LV lateral wall in patients with DCM and LBBB. Cardiac resynchronization therapy restores homogeneous myocardial glucose metabolism with less influence on perfusion.
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