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- W2083436729 abstract "One of the crucial pathogenic mechanisms in Alzheimers' disease (AD) is the accumulation of amyloid β-peptide (Aβ) in the brain according to the amyloid hypothesis. Aβ is generated by the β- (BACE 1) and γ-secretases which cleave amyloid precursor protein (APP) into Aβ fragments. Thus, these enzymes are promising targets for decreasing the Aβ load in AD and modifying the disease. However, γ-secretase also cleaves Notch and γ-secretase inhibitors cause abnormalities in rodents (gastrointestinal tract, spleen and thymus). Hence, inhibition of BACE 1 may be a better target for the treatment of AD but the experience with γ-secretase inhibitors demonstrate that it is very important to study the longer-term biological effects of BACE 1 inhibition in vivo. This is currently very difficult because the published BACE 1 inhibitors only cross the blood brain barrier to a limited degree. We hypothesised that the published BACE 1 inhibitors from Merck (merck 3) and Eli Lilly (LY2434074) may be p-glycoprotein (pgp) substrates. The efficacy of these BACE1 inhibitors was measured in vitro with IC50 of 10 nM and 80 nM, respectively. Moreover, we treated different wildtype mouse strains and pgp-knockout mice with the inhibitors and analysed the brains for both drug exposure and Aβ1–40 levels. In wildtype mice strains, the brain content of the LY2434074 compound was lower compared to PgP mice and accordingly only partial inhibition of BACE 1, as measured by Aβ1–40 levels, was observed. Interestingly, a full dose response analysis om PgP mice showed the maximal inhibitory effect of both BACE 1 inhibitors to be approximately 50%. In contrast, a gamma secretase inhibitor from Eli Lilly showed higher degree of inhibition (90%). We conclude that PgP-knock-out mice can be used for the characterization of the biology of BACE 1 inhibition in the CNS." @default.
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- W2083436729 date "2008-07-01" @default.
- W2083436729 modified "2023-09-27" @default.
- W2083436729 title "P1-082: Inhibition of Bace and Abeta1-40 production in PgP knockout mice" @default.
- W2083436729 doi "https://doi.org/10.1016/j.jalz.2008.05.668" @default.
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