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Updated: Oct 8, 2026
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Fungally Derived Isoquinoline Demonstrates Inducer-Specific Tau Aggregation Inhibition
David J Ingham1, Bryce R Blankenfeld1, Shibin Chacko2
1Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, United States.
Abstract:
The microtubule-associated protein tau promotes the stabilization of the axonal cytoskeleton in neurons. In several neurodegenerative diseases, such as Alzheimer's disease, tau has been found to dissociate from microtubules, leading to the formation of pathological aggregates that display an amyloid fibril-like structure. Recent structural studies have shown that the tau filaments isolated from different neurodegenerative disorders have structurally distinct fibril cores that are specific to the disease. These "strains" of tau fibrils appear to propagate between neurons in a prion-like fashion that maintains their initial template structure. In addition, the strains isolated from diseased tissue appear to have structures that are different from those made by the most commonly used in vitro modeling inducer molecule, heparin. The structural differences among strains in different diseases and in vitro-induced tau fibrils may contribute to recent failures in clinical trials of compounds designed to target tau pathology. This study identifies an isoquinoline compound (ANTC-15) isolated from the fungus Aspergillus nidulans that can both inhibit filaments induced by arachidonic acid (ARA) and disassemble preformed ARA fibrils. When compared to a tau aggregation inhibitor currently in clinical trials (LMTX, LMTM, or TRx0237), ANTC-15 and LMTX were found to have opposing inducer-specific activities against ARA and heparin in vitro-induced tau filaments. These findings may help explain the disappointing results in translating potent preclinical inhibitor candidates to successful clinical treatments.
Insights
A novel compound, ANTC-15, inhibits and disassembles tau fibrils. This discovery may explain why some tau-targeting drugs fail in clinical trials due to differing tau strains.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Microtubule-associated protein tau stabilizes neuronal axons.
- In neurodegenerative diseases, tau detaches, forming pathological amyloid structures.
- Distinct tau fibril strains exist in different diseases and differ from in vitro models.
Purpose of the Study:
- To identify compounds that can inhibit and disassemble tau aggregates.
- To compare the activity of novel compounds with existing tau inhibitors.
- To understand how tau strain diversity impacts drug efficacy.
Main Methods:
- Isolation and characterization of an isoquinoline compound (ANTC-15) from Aspergillus nidulans.
- Testing ANTC-15's ability to inhibit and disassemble arachidonic acid (ARA)-induced tau filaments.
- Comparing ANTC-15's activity with LMTX against ARA- and heparin-induced tau filaments in vitro.
Main Results:
- ANTC-15 inhibits ARA-induced tau filament formation and disassembles preformed ARA fibrils.
- ANTC-15 and LMTX exhibit opposing inducer-specific activities against ARA and heparin tau filaments.
- Structural differences in tau strains may explain variable drug responses.
Conclusions:
- ANTC-15 is a potent inhibitor and disassembler of specific tau strains.
- Drug efficacy against tau pathology may depend on the specific disease-associated tau strain.
- Understanding tau strain diversity is crucial for developing effective treatments for neurodegenerative diseases.
