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Fungally Derived Isoquinoline Demonstrates Inducer-Specific Tau Aggregation Inhibition.

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.

SUBMITTER: Ingham DJ

PROVIDER: S-EPMC8173610 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) affect 6 million Americans, and they are projected to have an estimated health care cost of $355 billion for 2021. A histopathological hallmark of AD and many ADRDs is the aberrant intracellular accumulation of the microtubule-associated protein tau. These neurodegenerative disorders that contain tau aggregates are collectively known as tauopathies, and recent structural studies have shown that different tauopathies are characterized by different "strains" of tau filaments. In addition, mutations in the gene that encodes for tau protein expression have been associated with a group of tauopathies known as frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17 or familial frontotemporal dementia). In vitro studies often use small molecules to induce tau aggregation as tau is extremely soluble and does not spontaneously aggregate under typical laboratory conditions, and the use of authentic filaments to conduct in vitro studies is not feasible. This study highlights how different inducer molecules can have fundamental disparities to how disease-related mutations affect the aggregation dynamics of tau. Using three different classes of tau aggregation inducer molecules, we characterized disease-relevant mutations in tau's PGGG motifs at positions P301S, P332S, and P364S. When comparing these mutations to wild-type tau, we found that depending on the type of inducer molecule used, we saw fundamental differences in total aggregation, aggregation kinetics, immunoreactivity, and filament numbers, length, and width. These data are consistent with the possibility that different tau aggregation inducer molecules make different structural polymorphs, although this possibility would need to be confirmed by high-resolution techniques such as cryo-electron microscopy. The data also show that disease-associated missense mutations in tau impact tau aggregation differently depending on the mechanism of aggregation induction.

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Fungally Derived Isoquinoline Demonstrates Inducer-Specific Tau Aggregation Inhibition.

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