Abstract
A central characteristic of Alzheimer’s disease (AD) and other tauopathies is the accumulation of aggregated and misfolded Tau deposits in the brain. Tau-targeting therapies for AD have been unsuccessful in patients to date. Here we show that human polymerase δ-interacting protein 2 (PolDIP2) interacts with Tau. With a set of complementary methods, including thioflavin-T-based aggregation kinetic assays, Tau oligomer-specific dot-blot analysis, and single oligomer/fibril analysis by atomic force microscopy, we demonstrate that PolDIP2 inhibits Tau aggregation and amyloid fibril growth in vitro. The identification of PolDIP2 as a potential regulator of cellular Tau aggregation should be considered for future Tau-targeting therapeutics.
Highlights
Aging-related neurodegenerative diseases are a worldwide problem with limited therapeutical solutions
These Tau oligomers provide seeds that can lead to Tau misfolding and further aggregation into insoluble fibrils, and the development of Taurelated pathologies, or tauopathies
We show that PolDIP2 inhibits aggregation and amyloid fibril development of the Tau protein
Summary
Aging-related neurodegenerative diseases are a worldwide problem with limited therapeutical solutions. Tau is dissociated from the microtubules and self-aggregates to form soluble oligomers [4,5] These Tau oligomers provide seeds that can lead to Tau misfolding and further aggregation into insoluble fibrils, and the development of Taurelated pathologies, or tauopathies. For these reasons, Tau is a promising target for the development of drugs that would prevent the formation of neurofibrillary lesions. Polymerase δ-interacting protein 2 (PolDIP2, known as PDIP38) has recently been identified as a specific binding partner of Tau monomers, but not Tau oligomers or fibrils [6]. We show that PolDIP2 inhibits aggregation and amyloid fibril development of the Tau protein
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