Klaus Fuchs

Presenilin‐dependent γ‐secretase processing of β‐amyloid precursor protein at a site corresponding to the S3 cleavage of Notch

The presenilin (PS)‐dependent site 3 (S3) cleavage of Notch liberates its intracellular domain (NICD), which is required for Notch signaling. The similar γ‐secretase cleavage of the β‐amyloid precursor protein (βAPP) results in the secretion of amyloid β‐peptide (Aβ). However, little is known about the corresponding C‐terminal cleavage product (CTFγ). We have now identified CTFγ in brain tissue, in living cells, as well as in an in vitro system. Generation of CTFγ is facilitated by PSs, since a dominant‐negative mutation of PS as well as a PS gene knock out prevents its production. Moreover, γ‐secretase inhibitors, including one that is known to bind to PS, also block CTFγ generation. Sequence analysis revealed that CTFγ is produced by a novel γ‐secretase cut, which occurs at a site corresponding to the S3 cleavage of Notch.

PDE9 INHIBITION IMPROVES COGNITION IN MICE BY A MECHANISM DIFFERENT FROM THE ACETYLCHOLINE ESTERASE INHIBITOR DONEPEZIL

Selaginella delicatula a pteridophyte (popularly known as Sanjeevani) is reported to contain characteristic biflavonoids (amentoflavone) with various biological activities in vitro. In this study, we have tested the hypothesis whether Selaginella flavonoids (SF) possess the potential to abrogate the lipopolysaccharide (LPS)induced biochemical and phenotypic alterations in Drosophila and mice models. Methods: First regimen, mice provided prophylaxis with (SF, 25 & 50mg/kg/d, p.o., for 15d, n1⁄46) were challenged with LPS (0.5mg/kg/d, ip, last 5 days). Phenotypic manifestations were assessed by employing a battery of behavioral assays for dementia (elevated plus maze, Y-maze, Morris water maze, passive avoidance). Hippocampus region was subjected to biochemical assessments viz., mitochondrial dysfunction, oxidative stress and AChE activity. Second regimen, adult Drosophila (n1⁄425, 6 replicates) maintained on SF enriched diet (0.05-0.1%, 7 days), were challenged with LPS (200mg, filter discs) and subsequently subjected to behavioral and biochemical tests. Results:LPS exposure induced significant behavioral aberrations among mice as evident from mazes. The passive avoidance score was markedly reduced among the LPS mice indicating severe dementia traits. Interestingly, the extent of LPS-induced behavioral anomalies among mice given SF prophylaxis was significantly attenuated. Additionally SF mice exhibited reduced oxidative stress markers, nitric oxide levels, diminished AChE activity and improved mitochondrial membrane permeability. In the Drosophila we could reproduce the protective effects of SF prophylaxis as evidenced by diminished LPS-induced general aggressive behavior, oxidative markers and AChE activity. Conclusions:These in vivo data are suggestive of potent neuro-attenuatory propensity of Selaginella flavonoids against LPS-induced dementia in mice and Drosophila and merit further mechanistic investigations.

Effects of the bace1 inhibitor bi 1181181 and the anti-abeta antibody m266 on abeta in rat brain homogenate and CSF

mice compared with wild-type mice, were significantly attenuated in FMeC1-treated APPswe/PS1dE9 mice. In the in vitro study, both curcumin and FMeC1 modulated the formation of Ab aggregates, however, only FMeC1 significantly attenuated cell toxicity of Ab. Conclusions: These results indicated that FMeC1 treatment inhibited the cognitive deficits and reduced Ab deposition and glial cell activation in the brain in APPswe/PS1dE9 mice. Thus we propose that the C-4 curcumin derivative, FMeC1 may be a useful candidate for preventing AD.