Illuminating Tau Aggregates: Multiscale Approaches for Detection, Imaging, and Understanding

ABSTRACT Tau protein aggregation is a hallmark of a diverse group of neurodegenerative disorders known as tauopathies, including Alzheimer's disease, Pick's disease, and progressive supranuclear palsy. These disorders are characterized by the misfolding of tau into β‐sheet‐rich fibrils, disrupting neuronal function and contributing to disease progression. This review presents a comprehensive overview of the advances in molecular imaging that have deepened our understanding of tau pathology. We begin by examining tau's domain architecture, isoform diversity, and aggregation mechanisms, highlighting the central role of the microtubule‐binding region in fibril formation. The review then explores the structural polymorphism of tau fibrils across tauopathies, emphasizing the significance of cryo‐electron microscopy in resolving disease‐specific conformers. We discuss the fluorescence and radioimaging as powerful tools for detecting tau aggregates at the nanoscale. Particular focus is given to the development of tau‐selective fluorescent probes and positron emission tomography tracers, detailing their design strategies, binding mechanisms, and diagnostic potential. Emerging approaches such as super‐resolution imaging and sensor arrays are also considered for their ability to enhance sensitivity and specificity. By integrating insights from structural biology, chemical imaging, and molecular neuroscience, this review provides a multiscale framework for understanding tau aggregation and its implications for diagnosis and therapeutic intervention.