| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T1 |
0-132 |
DRI_Background |
denotes |
RAC1 inhibition targets amyloid precursor protein processing by gamma-secretase and decreases Abeta production in vitro and in vivo. |
| T2 |
133-353 |
DRI_Background |
denotes |
beta-Amyloid peptides (Abeta) that form the senile plaques of Alzheimer disease consist mainly of 40- and 42-amino acid (Abeta 40 and Abeta 42) peptides generated from the cleavage of the amyloid precursor protein (APP). |
| T3 |
354-515 |
DRI_Background |
denotes |
Generation of Abeta involves beta-secretase and gamma-secretase activities and is regulated by membrane trafficking of the proteins involved in Abeta production. |
| T4 |
516-606 |
DRI_Approach |
denotes |
Here we describe a new small molecule, EHT 1864, which blocks the Rac1 signaling pathways. |
| T5 |
607-739 |
DRI_Unspecified |
denotes |
In vitro, EHT 1864 blocks Abeta 40 and Abeta 42 production but does not impact sAPPalpha levels and does not inhibit beta-secretase. |
| T6 |
740-858 |
DRI_Background |
denotes |
Rather, EHT 1864 modulates APP processing at the level of gamma-secretase to prevent Abeta 40 and Abeta 42 generation. |
| T7 |
859-1024 |
DRI_Challenge |
denotes |
This effect does not result from a direct inhibition of the gamma-secretase activity and is specific for APP cleavage, since EHT 1864 does not affect Notch cleavage. |
| T8 |
1025-1228 |
DRI_Unspecified |
denotes |
In vivo, EHT 1864 significantly reduces Abeta 40 and Abeta 42 levels in guinea pig brains at a threshold that is compatible with delaying plaque accumulation and/or clearing the existing plaque in brain. |
| T9 |
1229-1374 |
DRI_Background |
denotes |
EHT 1864 is the first derivative of a new chemical series that consists of candidates for inhibiting Abeta formation in the brain of AD patients. |
| T10 |
1375-1518 |
DRI_Outcome |
denotes |
Our findings represent the first pharmacological validation of Rac1 signaling as a target for developing novel therapies for Alzheimer disease. |
