Genetic and multi‐omic risk assessment of Alzheimer's disease implicates core associated biological domains

Alzheimer s & Dementia Translational Research & Clinical Interventions, Год журнала: 2024, Номер 10(2)

Опубликована: Апрель 1, 2024

Abstract INTRODUCTION Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence mixed pathologies, potential subtypes, numerous associated endophenotypes. Beyond difficulty designing treatments that address core pathological characteristics disease, therapeutic development challenged by uncertainty which endophenotypic areas specific targets implicated those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large‐scale open science efforts have produced multiple omic analyses both risk relevance biological process involvement genes across genome. METHODS Here we report an informatic pipeline draws from genetic association studies, predicted variant impact, linkage phenotypes create a score. This paired multi‐omic score utilizing extensive sets transcriptomic proteomic studies identify system‐level changes in expression AD. These two elements combined constitute our target ranks AD genome‐wide. The ranked are organized into space through 19 domains described genetics genomics accompanying literature. constructed exhaustive Gene Ontology (GO) term compilations, allowing automated assignment objectively defined disease‐associated biology. rank‐and‐organize approach, performed genome‐wide, allows characterization aggregations domains. RESULTS top AD‐risk‐associated Synapse, Immune Response, Lipid Metabolism, Mitochondrial Structural Stabilization, Proteostasis, slightly lower levels enrichment present within other 13 DISCUSSION provides objective methodology localize drill down most significantly GO terms annotated targets.

Язык: Английский

Fused Tetrahydroquinolines Are Interfering with Your Assay

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(21), С. 14434 - 14446

Опубликована: Окт. 24, 2023

Tricyclic tetrahydroquinolines (THQs) have been repeatedly reported as hits across a diverse range of high-throughput screening (HTS) campaigns. The activities these compounds, however, are likely due to reactive byproducts that interfere with the assay. As lesser studied class pan-assay interference mechanism by which fused THQs react protein targets remains largely unknown. During HTS follow-up, we characterized behavior and stability several tricyclic THQs. We synthesized key analogues pinpoint cyclopentene ring double bond source reactivity found compounds degrade in solution under standard laboratory conditions days. Importantly, observations make it THQs, ubiquitously within small molecule libraries, unlikely intact parent compounds. urge deprioritization tricylic THQ follow-up caution against investment resources on problematic

Язык: Английский

Open drug discovery in Alzheimer's disease

Alzheimer s & Dementia Translational Research & Clinical Interventions, Год журнала: 2023, Номер 9(2)

Опубликована: Апрель 1, 2023

Alzheimer's disease (AD) drug discovery has focused on a set of highly studied therapeutic hypotheses, with limited success. The heterogeneous nature AD processes suggests that more diverse, systems-integrated strategy may identify new hypotheses. Although many target hypotheses have arisen from systems-level modeling human disease, in practice and for reasons, it proven challenging to translate them into pipelines. First, implicate protein targets and/or biological mechanisms are under-studied, meaning there is paucity evidence inform experimental strategies as well high-quality reagents perform them. Second, predicted act concert, requiring adaptations how we characterize targets. Here posit the development open distribution informatic outputs-termed enabling packages (TEPs)-will catalyze rapid evaluation emerging by parallel, independent, unencumbered research.

Язык: Английский