Integrated Platform to Support Drug Development Against Protein-Aggregation-Related Neurodegenerative Diseases

Pathological protein aggregates are critical hallmarks of most neurodegenerative diseases (NDDs) and serve as primary targets for developing disease-modifying therapies (DMTs). To expedite the translation of scientific discoveries into real-world therapies for NDDs, we have established an integrated platform focused on protein-aggregation-related neurodegenerative diseases. This platform incorporates both in vitro assays and in vivo disease models, supporting in vitro screening and efficacy testing, as well as in vivo neuropharmacology. In vitro assay capabilities include measuring protein aggregation in a cell-free system (Aβ42 and Tau) and cell-based assays (Aβ42, Tau and α-synuclein). These protein aggregates exhibit toxicity, such as Aβ42 oligomer decreases cell viability in vitro in a dosage dependent manner. Stress granules (SGs) are also considered as key contributors to the protein aggregates, which can be visualized by the stress granule marker G3BP1. The in vivo animal disease models, which exhibit pathological protein aggregates, include models for Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease (HD). Pathological staining techniques identify the protein aggregates of Aβ, Tau, α-synuclein, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and mutant huntingtin (mHTT). In addition to behavioral abnormalities such as cognitive dysfunction and/or motor impairment, examined by Morris water maze, novel object recognition, rotarod, catwalk, these models also exhibit universally increased neuroinflammation, indicated by activated microglia and astrocytes. In summary, the integrated platform for protein-aggregation-related neurodegenerative diseases can support drug development against NDDs and will serve as an end-to-end center for screening and efficacy testing of various modalities, including small molecules, peptides, oligonucleotides, bi-functional molecules, and vaccines.

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