Tau Protein and Tauopathies: Exploring Tau Protein‐Protein and Microtubule Interactions, Cross‐Interactions and Therapeutic Strategies.

Abstract Tau, a microtubule‐associated protein (MAP), is essential to maintaining neuronal stability and function in the healthy brain. However, aberrant modifications and pathological aggregations of Tau are implicated in various neurodegenerative disorders, collectively known as tauopathies. The most common Tauopathy is Alzheimer's Disease (AD) counting nowadays more than 60 million patients worldwide. This comprehensive review delves into the multifaceted realm of Tau protein, puzzling out its intricate involvement in both physiological and pathological roles. Emphasis is put on Tau Protein–Protein Interactions (PPIs), depicting its interaction with tubulin, microtubules and its cross‐interaction with other proteins such as Aβ1‐42, α‐synuclein, and the chaperone machinery. In the realm of therapeutic strategies, an overview of diverse possibilities is presented with their relative clinical progresses. The focus is mostly addressed to Tau protein aggregation inhibitors including recent small molecules, short peptides and peptidomimetics with specific focus on compounds that showed a double anti aggregative activity on both Tau protein and Aβ amyloid peptide. This review amalgamates current knowledge on Tau protein and evolving therapeutic strategies, providing a comprehensive resource for researchers seeking to deepen their understanding of the Tau protein and for scientists involved in the development of new peptide‐based anti‐aggregative Tau compounds.