Screening Techniques for Drug Discovery in Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible impairment of memory and other cognitive functions of the aging brain. Pathways such as amyloid beta neurotoxicity, tau pathogenesis and neuroinflammatory have been used to understand AD, despite not knowing the definite molecular mechanism which causes this progressive disease. This review attempts to summarize the small molecules that target these pathways using various techniques involving high-throughput screening, molecular modeling, custom bioassays, and spectroscopic detection tools. Novel and evolving screening methods developed to advance drug discovery initiatives in AD research are also highlighted.

Tackling neurodegeneration in vitro with omics: a path towards new targets and drugs

“…The experimental screening of chemical agents in vitro represents an integral part of the early drug discovery pipeline ( Hughes et al, 2011 ). In the last decades, numerous biochemical and cell-based in vitro assays have been developed for the high-throughput investigation of a compounds’ ability to interfere with distinct traits of the pathology underlying NDDs ( Aldewachi et al, 2021 ; Maniam and Maniam, 2024 ). As concerns bioassays on isolated targets, different miniaturized alternatives have been established for High-Throughput Screening (HTS) of small molecules active in distinct pathways in AD/PD, i.e., UV–Vis, chemiluminescence- or fluorescence-based approaches to screen for binding partners of Aβ isoforms [e.g., ThioflavinT assay ( Lee S. et al, 2023 )] and tau oligomers, as well as of BACE1 (beta-secretase 1), TDP-43 ( Buratti et al, 2013 ), ApoE ( Chen et al, 2012 ), which among others include Fluorescence Resonance Energy Transfer (FRET) assays [e.g., AlphaScreen ( Ren et al, 2013 )].…”

“…As concerns bioassays on isolated targets, different miniaturized alternatives have been established for High-Throughput Screening (HTS) of small molecules active in distinct pathways in AD/PD, i.e., UV–Vis, chemiluminescence- or fluorescence-based approaches to screen for binding partners of Aβ isoforms [e.g., ThioflavinT assay ( Lee S. et al, 2023 )] and tau oligomers, as well as of BACE1 (beta-secretase 1), TDP-43 ( Buratti et al, 2013 ), ApoE ( Chen et al, 2012 ), which among others include Fluorescence Resonance Energy Transfer (FRET) assays [e.g., AlphaScreen ( Ren et al, 2013 )]. In addition, cell-based high-content imaging screening (HCS) alternatives have been reported for the automated analysis of cell morphology changes and their drug-induced dynamics ( Ofengeim et al, 2012 ), as well as mass-spectrometry (MS)-based HTS methods able to visualize protein aggregation in ex vivo drug-exposed brain section ( Yoshimi et al, 2015 ) and other phenotypic options ( Maniam and Maniam, 2024 ). Although such approaches provided the field with novel insights on potential drug candidates and interesting targets for NDDs drug development, they do not offer an holistic overview of cellular responses and phenotypic changes upon perturbation.…”