Matches in SemOpenAlex for { <https://semopenalex.org/work/W2897010180> ?p ?o ?g. }
Showing items 1 to 77 of
77
with 100 items per page.
- W2897010180 abstract "Alzheimer's disease (AD) progression is associated with the spread of tau pathological aggregates within the brain in a highly reproducible pattern that is used to stage the disease. We have shown that extracellular tau oligomers are cytotoxic to neurons, inhibit long-term potentiation and impair memory formation in mice. Tau oligomers have also been shown to transmit tau pathology to neighboring neurons by seeding tau misfolding and aggregation. We have developed novel assays to select and optimize small molecules inhibiting tau self-association into oligomers to block the aggregation pathway at its start. An optimized compound from our lead series was selected for in vivo evaluation. The lead did not exhibit any genotoxic effects in a mini-AMES test, is not a substrate or inhibitor of P-gp, and had little effect on hERG. In vitro pharmacological profiling was performed on a panel of 47 targets but did not identify undesirable off-target activity. Pharmacokinetic studies and a 5-day toxicity study in mice were performed showing good exposure in the brain and good tolerability. A blinded efficacy study was performed in the human tau mouse model. Male and female mice (n=100) were separated into four groups and treated for four months starting at three months of age with vehicle, 10 mg/kg, 40 mg/kg or 100 mg/kg of the lead compound milled into feed. Mice did not show any adverse events related to the compound. Total self-associated tau, as measured by mono-antibody ELISA, was reduced with statistical significance. Male htau mice developed significantly more insoluble tau pathology than female mice. The primary endpoint, statistically significant reduction of insoluble tau, was achieved in male mice with a maximum effective dose of 40 mg/kg. Phosphorylated insoluble tau was also significantly reduced at three distinct epitopes. These results demonstrate that our lead compound reduced self-association of tau and inhibited formation of insoluble tau aggregates. The activity translated from in vitro and cellular assays to an in vivo model of tau aggregation validating our screening approach and showing that targeting oligomer formation can inhibit the entire tau aggregation pathway. In vitro safety screens also indicate further advancement of the program." @default.
- W2897010180 created "2018-10-26" @default.
- W2897010180 creator A5030631021 @default.
- W2897010180 creator A5030789444 @default.
- W2897010180 creator A5060846269 @default.
- W2897010180 creator A5068324801 @default.
- W2897010180 creator A5080474136 @default.
- W2897010180 creator A5082824835 @default.
- W2897010180 date "2018-07-01" @default.
- W2897010180 modified "2023-10-16" @default.
- W2897010180 title "P4‐222: IN VIVO EFFICACY OF A SMALL MOLECULE INHIBITOR OF TAU OLIGOMER FORMATION IN HTAU MICE" @default.
- W2897010180 doi "https://doi.org/10.1016/j.jalz.2018.07.043" @default.
- W2897010180 hasPublicationYear "2018" @default.
- W2897010180 type Work @default.
- W2897010180 sameAs 2897010180 @default.
- W2897010180 citedByCount "1" @default.
- W2897010180 countsByYear W28970101802020 @default.
- W2897010180 crossrefType "journal-article" @default.
- W2897010180 hasAuthorship W2897010180A5030631021 @default.
- W2897010180 hasAuthorship W2897010180A5030789444 @default.
- W2897010180 hasAuthorship W2897010180A5060846269 @default.
- W2897010180 hasAuthorship W2897010180A5068324801 @default.
- W2897010180 hasAuthorship W2897010180A5080474136 @default.
- W2897010180 hasAuthorship W2897010180A5082824835 @default.
- W2897010180 hasConcept C112705442 @default.
- W2897010180 hasConcept C150903083 @default.
- W2897010180 hasConcept C170493617 @default.
- W2897010180 hasConcept C178790620 @default.
- W2897010180 hasConcept C185592680 @default.
- W2897010180 hasConcept C197934379 @default.
- W2897010180 hasConcept C202751555 @default.
- W2897010180 hasConcept C207001950 @default.
- W2897010180 hasConcept C25274449 @default.
- W2897010180 hasConcept C2777752112 @default.
- W2897010180 hasConcept C2778375690 @default.
- W2897010180 hasConcept C28406088 @default.
- W2897010180 hasConcept C29730261 @default.
- W2897010180 hasConcept C55493867 @default.
- W2897010180 hasConcept C71924100 @default.
- W2897010180 hasConcept C86803240 @default.
- W2897010180 hasConcept C98274493 @default.
- W2897010180 hasConceptScore W2897010180C112705442 @default.
- W2897010180 hasConceptScore W2897010180C150903083 @default.
- W2897010180 hasConceptScore W2897010180C170493617 @default.
- W2897010180 hasConceptScore W2897010180C178790620 @default.
- W2897010180 hasConceptScore W2897010180C185592680 @default.
- W2897010180 hasConceptScore W2897010180C197934379 @default.
- W2897010180 hasConceptScore W2897010180C202751555 @default.
- W2897010180 hasConceptScore W2897010180C207001950 @default.
- W2897010180 hasConceptScore W2897010180C25274449 @default.
- W2897010180 hasConceptScore W2897010180C2777752112 @default.
- W2897010180 hasConceptScore W2897010180C2778375690 @default.
- W2897010180 hasConceptScore W2897010180C28406088 @default.
- W2897010180 hasConceptScore W2897010180C29730261 @default.
- W2897010180 hasConceptScore W2897010180C55493867 @default.
- W2897010180 hasConceptScore W2897010180C71924100 @default.
- W2897010180 hasConceptScore W2897010180C86803240 @default.
- W2897010180 hasConceptScore W2897010180C98274493 @default.
- W2897010180 hasIssue "7S_Part_29" @default.
- W2897010180 hasLocation W28970101801 @default.
- W2897010180 hasOpenAccess W2897010180 @default.
- W2897010180 hasPrimaryLocation W28970101801 @default.
- W2897010180 hasRelatedWork W1491964893 @default.
- W2897010180 hasRelatedWork W1998587742 @default.
- W2897010180 hasRelatedWork W2004556784 @default.
- W2897010180 hasRelatedWork W2037576960 @default.
- W2897010180 hasRelatedWork W2094219250 @default.
- W2897010180 hasRelatedWork W2379311614 @default.
- W2897010180 hasRelatedWork W2388069209 @default.
- W2897010180 hasRelatedWork W2582907174 @default.
- W2897010180 hasRelatedWork W2753834235 @default.
- W2897010180 hasRelatedWork W4253098345 @default.
- W2897010180 hasVolume "14" @default.
- W2897010180 isParatext "false" @default.
- W2897010180 isRetracted "false" @default.
- W2897010180 magId "2897010180" @default.
- W2897010180 workType "article" @default.