Inhibition of Amyloid-β Aggregation and Caspase-3 Activation by the \u3ci\u3eGinkgo biloba\u3c/i\u3e Extract EGb761

Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, has been used in clinical trials for its beneficial effects on brain functions, particularly in connection with age-related dementias and Alzheimer\u27s disease (AD). Substantial experimental evidence indicates that EGb761 protects against neuronal damage from a variety of insults, but its cellular and molecular mechanisms remain unknown. Using a neuroblastoma cell line stably expressing an AD-associated double mutation, we report that EGb761 inhibits formation of amyloid-β (Aβ) fibrils, which are the diagnostic, and possibly causative, feature of AD. The decreased Aβ fibrillogenesis in the presence of EGb761 was observed both in the conditioned medium of this Aβ-secreting cell line and in solution in vitro. In the cells, EGb761 significantly attenuated mitochondrion-initiated apoptosis and decreased the activity of caspase 3, a key enzyme in the apoptosis cell-signaling cascade. These results suggest that (i) neuronal damage in AD might be due to two factors: a direct Aβ toxicity and the apoptosis initiated by the mitochondria; and (ii) multiple cellular and molecular neuroprotective mechanisms, including attenuation of apoptosis and direct inhibition of Aβ aggregation, underlie the neuroprotective effects of EGb761

The 1.6 micron near infrared nuclei of 3C radio galaxies: Jets, thermal emission or scattered light?

Using HST NICMOS 2 observations we have measured 1.6-micron near infrared nuclear luminosities of 100 3CR radio galaxies with z<0.3, by modeling and subtracting the extended emission from the host galaxy. We performed a multi-wavelength statistical analysis (including optical and radio data) of the properties of the nuclei following classification of the objects into FRI and FRII, and LIG (low-ionization galaxies), HIG (high-ionization galaxies) and BLO (broad-lined objects) using the radio morphology and optical spectra, respectively. The correlations among near infrared, optical, and radio nuclear luminosity support the idea that the near infrared nuclear emission of FRIs has a non-thermal origin. Despite the difference in radio morphology, the multi-wavelength properties of FRII LIG nuclei are statistically indistinguishable from those of FRIs, an indication of a common structure of the central engine. All BLOs show an unresolved near infrared nucleus and a large near infrared excess with respect to FRII LIGs and FRIs of equal radio core luminosity. This requires the presence of an additional (and dominant) component other than the non-thermal light. Considering the shape of their spectral energy distribution, we ascribe the origin of their near infrared light to hot circumnuclear dust. A near infrared excess is also found in HIGs, but their nuclei are substantially fainter than those of BLO. This result indicates that substantial obscuration along the line-of-sight to the nuclei is still present at 1.6 micron. Nonetheless, HIGs nuclei cannot simply be explained in terms of dust obscuration: a significant contribution from light reflected in a circumnuclear scattering region is needed to account for their multiwavelength properties.Comment: 20 pages, 16 figures. Accepted for publication on Ap

Lowering β-Amyloid Levels Rescues Learning and Memory in a Down Syndrome Mouse Model

β-amyloid levels are elevated in Down syndrome (DS) patients throughout life and are believed to cause Alzheimer's disease (AD) in adult members of this population. However, it is not known if β-amyloid contributes to intellectual disability in younger individuals. We used a γ-secretase inhibitor to lower β-amyloid levels in young mice that model DS. This treatment corrected learning deficits characteristic of these mice, suggesting that β-amyloid-lowering therapies might improve cognitive function in young DS patients

An investigation of the effects of fuel composition on combustion characteristics in a T-63 combustor

A T63 combustor was instrumented to allow measurement ofcenterline distributions of temperature and soot size and concentration using water-cooled probes. Three-wavelength light transmission measurements were also made at two locations to determine the mean soot size and NOx concentrations were measured in the exhaust duct. Five fuels of varying composition were used in the combustor and initial tests were conducted using two smoke-suppressant fuel additives. The data indicated that the aft region of the combustor contained a large, low temperature recirculation zone, surrounded by an annular region of higher temperature and lower soot concentration. Light transmissionn measurements appeared to yield reasonable particle size data when compared to collected samples. However, the extent of agglomeration in the collection probes was unknown. Smoke-suppressant fuel additives were found to have reduced effectiveness in the present test series, apparently due to unheated inlet air which was employed. NOX levels increased significantly with increasing combustor exhaust temperature (or fuel-air ratio). Soot concentration increased and transmittance decreased with increasing fuel-air ratio. The mean soot particle size was found to be between 0.21 and 0.26 micronns, independent of fuel composition and fuel-air ratioNaval Air Propulsion Centerhttp://archive.org/details/investigationofe00dubeN6237685WR00020N

Dynamin 1 regulates amyloid generation through modulation of BACE-1.

BACKGROUND: Several lines of investigation support the notion that endocytosis is crucial for Alzheimer's disease (AD) pathogenesis. Substantial evidence have already been reported regarding the mechanisms underlying amyloid precursor protein (APP) traffic, but the regulation of beta-site APP-Cleaving Enzyme 1 (BACE-1) distribution among endosomes, TGN and plasma membrane remains unclear. Dynamin, an important adaptor protein that controls sorting of many molecules, has recently been associated with AD but its functions remain controversial. Here we studied possible roles for dynamin 1 (dyn1) in Aβ biogenesis. PRINCIPAL FINDINGS: We found that genetic perturbation of dyn1 reduces both secreted and intracellular Aβ levels in cell culture. There is a dramatic reduction in BACE-1 cleavage products of APP (sAPPβ and βCTF). Moreover, dyn1 knockdown (KD) leads to BACE-1 redistribution from the Golgi-TGN/endosome to the cell surface. There is an increase in the amount of surface holoAPP upon dyn1 KD, with resultant elevation of α-secretase cleavage products sAPPα and αCTF. But no changes are seen in the amount of nicastrin (NCT) or PS1 N-terminal fragment (NTF) at cell surface with dyn1 KD. Furthermore, treatment with a selective dynamin inhibitor Dynasore leads to similar reduction in βCTF and Aβ levels, comparable to changes with BACE inhibitor treatment. But combined inhibition of BACE-1 and dyn1 does not lead to further reduction in Aβ, suggesting that the Aβ-lowering effects of dynamin inhibition are mainly mediated through regulation of BACE-1 internalization. Aβ levels in dyn1(-/-) primary neurons, as well as in 3-month old dyn1 haploinsufficient animals with AD transgenic background are consistently reduced when compared to their wildtype counterparts. CONCLUSIONS: In summary, these data suggest a previously unknown mechanism by which dyn1 affects amyloid generation through regulation of BACE-1 subcellular localization and therefore its enzymatic activities

A selective dynamin inhibitor Dynasore reduces βCTF and Aβ levels.

<p>A) N2a 695 cells were treated with dynasore at 10 µM or BACE Inhibitor IV at 15µM before subjected for further analysis. Levels of βCTF and Aβ were determined and significant reductions were observed upon dynasore or BACE inhibitor treatment, as compared to control (*<i>p</i><0.05; **, <i>p</i><0.001). Protein levels were normalized to β-actin and expressed as percentage of control. Data were collected in duplicate or triplicate from three independent experiments. B) Dyn1 KD fibroblast cells were treated with tamoxifen (to induce dyn1 knockdown), BACE inhibitor IV or combination of both (top panels). Levels of Aβ₄₀ in the media are determined by sandwich ELISA analysis (**<i>p</i><0.001 comparing each treatment or combination to control). Alternatively cells were treated with dynasore, or BACE inhibitor IV or combination of both (bottom panels). Levels of Aβ₄₀ in the media are determined by sandwich ELISA analysis (**<i>p</i><0.001 comparing each treatment or combination to control).</p