Near‐Infrared Fluorescent PROTAC Enables Theranostic Imaging and Selective Tau Degradation in Alzheimer's Disease

The hyperphosphorylated Tau (p‐Tau) protein plays a central role in the pathogenesis of Alzheimer's disease (AD) by driving neurofibrillary tangle formation and neuronal dysfunction. While proteolysis targeting chimeras (PROTACs) offer a promising approach for directly eliminating pathogenic proteins, their real‐time visualization in living systems remains challenging. Here, we report the rational design and synthesis of a series of near‐infrared (NIR) fluorescent Tau‐targeting degraders that integrate theranostic imaging with targeted protein degradation. Among them, compound D9 emerges as a dual‐functional degrader capable of both high‐contrast fluorescence tracking and potent Tau clearance at 10 nM. Mechanistic investigations indicate that D9 induces Tau degradation through activation of the ubiquitin–proteasome system (UPS), as confirmed by inhibitor assays. Beyond Tau degradation, D9 also downregulates amyloid precursor protein (APP) and β‐amyloid (Aβ) expression, suggesting broader neuroprotective effects. In in vivo studies, D9 significantly promotes p‐Tau clearance and alleviates cognitive deficits in 3 ×Tg‐AD mice. These findings demonstrate that D9 represents a first‐in‐class NIR fluorescent PROTAC for theranostic imaging and targeted degradation of Tau, providing a powerful platform for visualizing degradation dynamics and developing next‐generation AD therapeutics.