PS dependent APP cleavage regulates glucosylceramide synthase and is affected in Alzheimer's disease.

BACKGROUND: Gangliosides were found to be associated with Alzheimer's disease (AD). Here we addressed a potential function of γ-secretase (presenilin) dependent cleavage of the amyloid-precursor-protein (APP) in the regulation of ganglioside de novo synthesis. METHODS: To identify a potential role of γ-secretase and APP in ganglioside de novo synthesis we used presenilin (PS) deficient and APP deficient cells and mouse brains, mutated PS as well as transgenic mice and AD post mortem brains. Changes in glucosylceramide synthase (GCS) activity were identified by incorporation of radiolabeled UDP-glucose in glucosylceramide, changes in gene expression via real-time PCR and Western blot analysis. Alterations in ganglioside levels were determined by thin layer chromatography and mass spectrometry. RESULTS: We found that PS and APP deficiency, in vitro and in vivo, resulted in increased GCS gene expression, elevated enzyme activity and thus increased glucosylceramide and total ganglioside level. Using a specific γ-secretase inhibitor revealed that PS proteolytic activity alters ganglioside homeostasis. By the use of mutated PS causing early onset AD in cell culture and transgenic mice we found that GCS is increased in AD, further substantiated by the use of AD post mortem brains, suffering from sporadic AD. CONCLUSION: APP processing regulates ganglioside de novo synthesis and is affected in AD.

On active control of laminar-turbulent transition on two-dimensional wings.

This paper gives an overview of drag reduction on aerofoils by means of active control of Tollmien-Schlichting (TS) waves. Wind-tunnel experiments at Mach numbers of up to M(x)=0.42 and model Reynolds numbers of up to Re(c)=2 × 10(6), as well as in-flight experiments on a wing glove at Mach numbers of M<0.1 and at a Reynolds number of Re(c)=2.4 × 10(6), are presented. Surface hot wires were used to detect the linearly growing TS waves in the transitional boundary layer. Different types of voice-coil- and piezo-driven membrane actuators, as well as active-wall actuators, located between the reference and error sensors, were demonstrated to be effective in introducing counter-waves into the boundary layer to cancel the travelling TS waves. A control algorithm based on the filtered-x least mean square (FxLMS) approach was employed for in-flight and high-speed wind-tunnel experiments. A model-predictive control algorithm was tested in low-speed experiments on an active-wall actuator system. For the in-flight experiments, a reduction of up to 12 dB (75% TS amplitude) was accomplished in the TS frequency range between 200 and 600 Hz. A significant reduction of up to 20 dB (90% TS amplitude) in the flow disturbance amplitude was achieved in high-speed wind-tunnel experiments in the fundamental TS frequency range between 3 and 8 kHz. A downstream shift of the laminar-turbulent transition of up to seven TS wavelengths is presented. The cascaded sensor-actuator arrangement given by Sturzebecher & Nitsche in 2003 for low-speed wind-tunnel experiments was able to shift the transition Δx=240 mm (18% x/c) downstream by a TS amplitude reduction of 96 per cent (30 dB). By using an active-wall actuator, which is much shorter than the cascaded system, a transition delay of seven TS wavelengths (16 dB TS amplitude reduction) was reached.

Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin.

Amyloid beta peptide (Abeta) has a key role in the pathological process of Alzheimer's disease (AD), but the physiological function of Abeta and of the amyloid precursor protein (APP) is unknown. Recently, it was shown that APP processing is sensitive to cholesterol and other lipids. Hydroxymethylglutaryl-CoA reductase (HMGR) and sphingomyelinases (SMases) are the main enzymes that regulate cholesterol biosynthesis and sphingomyelin (SM) levels, respectively. We show that control of cholesterol and SM metabolism involves APP processing. Abeta42 directly activates neutral SMase and downregulates SM levels, whereas Abeta40 reduces cholesterol de novo synthesis by inhibition of HMGR activity. This process strictly depends on gamma-secretase activity. In line with altered Abeta40/42 generation, pathological presenilin mutations result in increased cholesterol and decreased SM levels. Our results demonstrate a biological function for APP processing and also a functional basis for the link that has been observed between lipids and Alzheimer's disease (AD).