Year: 2019
Type: article
Abstract: Inhibitors of tau can act either directly by binding tau, or indirectly by affecting pathways that promote aggregation. Here, we dissect the mechanisms of two types of inhibitors: (1) capping peptides and (2) small molecule fibril binding compounds. Although both act directly by binding to aggregated tau, the mechanisms of seeding inhibition differ. Fibrils extracted from human tauopathy donors with Alzheimer's disease, Progressive Supranuclear Palsy, Chronic Traumatic Encephalopathy, and Cortical basal degeneration were used to seed HEK293 tau biosensor cells. Seeding inhibition was measured for capping peptides and small molecule fibril binding compounds. A panel of capping peptides that targets different surfaces of aggregated tau was designed using composite structures determined from high resolution crystal structures and published single particle cryoEM structures of human tau fibrils. Small molecule fibril binding compounds were identified by virtual docking, and binding was confirmed experimentally by isothermal titration calorimetry. A panel of capping inhibitors, each inhibitor of the panel targeting a different aggregation-prone surface of tau, differentially inhibited seeding by extracts from different tauopathies, and patterns of inhibitor sensitivity were diagnostic to the parent fibril polymorphs that were used for seeding. Small molecules exploited a different mechanism of action and pattern of inhibition. Unlike capping inhibitors, small molecules showed a broad window of activity blocking seeding by patient-derived fibril polymorphs from all tauopathies. Small molecules acted by disaggregating pathological tau fibrils, thereby eliminating proteopathic seeding. Our study highlights the contrasting utility of small molecule inhibitors and capping peptides, and suggests specific roles for each. Capping inhibitors showed a narrower window of seeding inhibition, suggesting a higher degree of specificity. Patterns of sensitivity to the panel of capping inhibitors were diagnostic to the parent fibril polymorphs that were used for seeding, and the tauopathies from which they derived. Owing to a narrower window of activity, capping inhibitors may be powerful diagnostic tools and targeted inhibitors of proteopathic seeding by tau. On the other hand, small molecules tested here showed great promise as there was little variability in the range of seeding inhibition that was observed across different tauopathies that we tested.
Source: Alzheimer s & Dementia
Author: Paul Seidler
Institution: University of California, Los Angeles
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2981276140