Faculty, Staff and Student Publications
Language
English
Publication Date
9-30-2025
Journal
Alzheimer's Research & Therapy
DOI
10.1186/s13195-025-01855-y
PMID
41029842
PMCID
PMC12482674
PubMedCentral® Posted Date
9-30-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Tau protein aggregates are a key pathological hallmark of Alzheimer's disease (AD) and are closely associated with cognitive decline and neurodegeneration. It is proposed that tau aggregates faithfully propagate throughout the brain by self-templating their disease-associated conformation onto natively-folded tau monomers, thereby inducing their aggregation and incorporation into growing fibrils. As such, the inhibition or modulation of tau seeding and aggregation represents a viable therapeutic strategy for AD and other tauopathies.
Methods: We have recently developed seed amplification assays (SAA) for the detection and amplification of small quantities of misfolded protein aggregates in various neurodegenerative diseases. In this article, we adapted the SAA technology to amplify the process of tau aggregation and seeding in AD brain samples. Using the Tau-SAA we screened two chemical libraries: one comprising over 20 suspected aggregation inhibitors and the other comprising over 200 FDA-approved, blood-brain barrier-permeable compounds from a commercial chemical library. We also performed secondary in vitro assays to confirm the activity of selected hits as well as determining the IC50 of the most active compounds.
Results: Our Tau-SAA detects the presence of tau seeds even after a 100-million-fold dilution of the initial inoculum. Examination of 26 postmortem brain samples from AD and control cases confirmed that our assay is specific for AD brain tau seeds. Screening of 220 compounds showed that approximately 57% of suspected aggregation inhibitors and ~ 3% of CNS-penetrant compounds inhibited over 75% of AD brain-templated tau aggregation.
Conclusions: In conclusion, our data suggests that Tau-SAA readily detects the presence of tau seeds in AD brains but not in controls, and that by amplifying AD brain tau seeds, the assay may serve as a valuable primary drug screening platform.
Keywords
tau Proteins, Humans, Alzheimer Disease, Brain, Drug Evaluation, Preclinical, Protein Aggregation, Pathological, Protein Aggregates, Tau, Alzheimer’s disease, Seed amplification assay, Drug screening, Therapeutics, Misfolded protein aggregates
Published Open-Access
yes
Recommended Citation
Gorski, Damian; Evans, Haley; Allison, Tyler; et al., "Design and Application of a Tau Seed Amplification Assay for Screening Inhibitors of Tau Seeding" (2025). Faculty, Staff and Student Publications. 6507.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6507
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