Amyloid-ß and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer's disease.

This study was designed to test the interaction between amyloid-ß and tau proteins as a determinant of metabolic decline in preclinical Alzheimer's disease (AD). We assessed 120 cognitively normal individuals with [18F]florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [18F]fluorodeoxyglucose ([18F]FDG) PET at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapir and [18F]FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [18F]florbetapir SUVR and CSF phosphorylated tau (p-tau) measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (P<0.001). In contrast, interactions using CSF amyloid-ß1-42 and total tau biomarkers did not associate with metabolic decline over a time frame of 24 months. The interaction found in this study further support the framework that amyloid-ß and hyperphosphorylated tau aggregates synergistically interact to cause downstream AD neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-ß plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-ß PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [18F]FDG as a biomarker of efficacy.

Rostral-Caudal Hippocampal Functional Convergence Is Reduced Across the Alzheimer's Disease Spectrum.

Beginning in the early stages of Alzheimer's disease (AD), the hippocampus reduces its functional connections to other cortical regions due to synaptic depletion. However, little is known regarding connectivity abnormalities within the hippocampus. Here, we describe rostral-caudal hippocampal convergence (rcHC), a metric of the overlap between the rostral and caudal hippocampal functional networks, across the clinical spectrum of AD. We predicted a decline in rostral-caudal hippocampal convergence in the early stages of the disease. Using fMRI, we generated resting-state hippocampal functional networks across 56 controls, 48 early MCI (EMCI), 35 late MCI (LMCI), and 31 AD patients from the Alzheimer's Disease Neuroimaging Initiative cohort. For each diagnostic group, we performed a conjunction analysis and compared the rostral and caudal hippocampal network changes using a mixed effects linear model to estimate the convergence and differences between these networks, respectively. The conjunction analysis showed a reduction of rostral-caudal hippocampal convergence strength from early MCI to AD, independent of hippocampal atrophy. Our results demonstrate a parallel between the functional convergence within the hippocampus and disease stage, which is independent of brain atrophy. These findings support the concept that network convergence might contribute as a biomarker for connectivity dysfunction in early stages of AD.

Regulation of skeletal muscle sarcolemmal ATP-dependent calcium transport by calmodulin and cAMP-dependent protein kinase.

Skeletal muscle sarcolemma preparations, predominantly in the form of inside-out vesicles, were obtained from porcine muscle by a LiBr-extraction procedure. In the presence of ATP, these preparations were able to accumulate 94 nmol Ca/mg protein after 20 min at 37 degrees C. Sarcolemmal calcium uptake was completely blocked by the calcium ionophore, A23187, but was unaffected by monovalent cation ionophores. Calcium uptake was markedly inhibited by vanadate, with an approximate Ki of 0.5 microM. Oxalate (5 mM) had little effect on the initial phase of calcium uptake, while inorganic phosphate, at concentrations up to 50 mM, had a significant stimulatory effect on sarcolemmal calcium uptake. In contrast to ATP, acetylphosphate had minimal ability and p-nitrophenylphosphate had no ability to support calcium uptake. The maximal initial velocity of skeletal muscle sarcolemmal calcium uptake was 10.0 nmol Ca mg-1 min-1 at 37 degrees C, with a K 1/2 for Ca2+ of 0.88 microM. Addition of either 1 microM calmodulin, or 5 microM cAMP and 0.1 mg/ml cAMP-dependent protein kinase, increased the Vmax to 12.5 and 12.8 nmol Ca mg-1 min-1, respectively, and decreased the K 1/2 for Ca2+ to 0.67 and 0.70 microM, respectively; simultaneous addition of calmodulin and cAMP-dependent protein kinase increased the Vmax to 15.2 nmol Ca mg-1 min-1 and further lowered the K 1/2 to 0.51 microM. When concentrations of NaCl from 10 to 60 mM were added to vesicles that had been loaded with calcium in the presence of ATP, an immediate release of calcium occurred. This process had an approximate K 1/2 for sodium of 10-20 mM and an approximate maximal rate of 50 nmol Ca mg-1 min-1. We conclude that skeletal muscle sarcolemma contains a cAMP-dependent protein kinase- and calmodulin-stimulatable ATP-dependent calcium transport, as well as a sodium: calcium exchange activity.

Bacteriocin Serratine-P as a biological tool in the control of fire blight Erwinia amylovora.

Fire blight, caused by the bacterium Erwinia amylovora (Burill Winslow et al.), is the most important bacterial disease in European pear growing. It can cause a lot of damage in some countries on apple and on pear trees in orchards and also in the fruit tree nurseries. In Belgium, the disease is present since 1972. Control of fire blight in Belgian fruit orchards is made on a broad basis of measurements in and around the fruit trees. The use of an antibiotic is allowed for application only during the primary blossom period under strict controlled regulations. The use of antobiotics in agriculture is strongly discussed on the European level today and will probably disappear in the near future. Therefore, the research on fire blight control concentrates on the possibilities of biological control with antagonistic bacteria such as Pantoea agglomerans (Erwinia herbicola), Bacillus subtilis or Pseudomonas syringae strain A 506. The use of Serratine-P, a phage tail-like bacteriocin, produced by Serratia plymiticum, shows an interesting antibacterial activity against Erwinia amylovora. Its mode of action consists in the perforation of the cytoplasmic membrane of the target cell, inducing perturbations in cellular exchanges and a final lysis of the bacterial cell. In this paper some trials are discussed on the use of Serratine-P at different doses and on different infection types on pear trees. The results indicate interesting protection possibilities on blossom- and fruit infections.

Increased skeletal muscle acetylcholinesterase activity in porcine malignant hyperthermia.

The content and distribution of acetylcholinesterase (AChE) activity in the skeletal muscle disorder malignant hyperthermia (MH) was examined. The AChE activity of sarcolemma membranes isolated from MH-susceptible (MHS) swine was increased twofold when compared with normal sarcolemma. The total AChE activity of muscle extracts was also doubled in MHS tissue; however, the relative distribution between low-salt extractable (globular forms) and high-salt extractable (asymmetric forms) AChE activities were similar in MHS and normal muscle. Our results suggest that, for as yet unexplained reasons, both the sarcolemmal and total AChE activity of skeletal muscle is increased in porcine MH.